Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

Open AccessPublished:August 31, 2018DOI:https://doi.org/10.1016/j.clnu.2018.08.032

      Summary

      Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function.
      Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system.
      Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise.

      Revision number

      YCLNU-D-17-01092R2.

      Keywords

      Abbreviations

      ATP
      Adenosinetriphosphate
      α-KGDH
      Alpha-ketoglutarate dehydrogenase
      cAMP
      Cyclic adenosinemonophosphate
      CoA
      Coenzyme A
      CoQ10
      Coenzyme Q10
      DNA
      Deoxyribonucleic acid
      FAD (H)
      Flavin adenine dinucleotide (reduced)
      FMN
      Flavin mononucleotide
      ICU
      Intensive Care Unit
      LA
      Lipoic acid
      mtDNA
      Mitochondrial deoxyribonucleic acid
      NAD (H)
      Nicotinamide adenine dinucleotide (reduced)
      NFκB
      Nuclear factor kappa B
      NRF
      Nuclear respiratory factor
      OXPHOS
      Oxidative phosphorylation
      PDH
      Pyruvate dehydrogenase
      PGC-1α
      Peroxisome proliferator-activated receptor-gamma coactivator
      Se
      Selenium
      TCA
      Tricarboxylic acid
      Tfam
      Mitochondrial transcription factor A
      TQ
      α-tocopheryl quinine
      RNS
      Reactive nitrogen species
      ROS
      Reactive oxygen species

      1. Introduction

      Due to improvements in clinical care and technological advancements, the number of patients surviving critical illness continues to rise, albeit often at the expense of health problems later in life [
      • Wischmeyer P.E.
      • San-Millan I.
      Winning the war against ICU-acquired weakness: new innovations in nutrition and exercise physiology.
      ]. Residual clinical motor and sensory neurologic deficits are extremely common in long-term survivors of critical illness and mortality rates are higher compared to age-matched controls [
      • Desai S.V.
      • Law T.J.
      • Needham D.M.
      Long-term complications of critical care.
      ,
      • Fletcher S.N.
      • Kennedy D.D.
      • Ghosh I.R.
      • Misra V.P.
      • Kiff K.
      • Coakley J.H.
      • et al.
      Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness.
      ]. Even five years after discharge from an intensive care unit (ICU), many patients suffer from impaired pulmonary function, muscle weakness and reduced ability to perform vigorous exercise [
      • Cheung A.M.
      • Tansey C.M.
      • Tomlinson G.
      • Diaz-Granados N.
      • Matté A.
      • Barr A.
      • et al.
      Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome.
      ,
      • Herridge M.S.
      • Tansey C.M.
      • Matté A.
      • Tomlinson G.
      • Diaz-Granados N.
      • Cooper A.
      • et al.
      Functional disability 5 Years after acute respiratory distress syndrome.
      ]. Next to these physical limitations, many survivors complain about social isolation, sexual dysfunction, anxiety, depression and other mental health problems [
      • Desai S.V.
      • Law T.J.
      • Needham D.M.
      Long-term complications of critical care.
      ,
      • Herridge M.S.
      • Tansey C.M.
      • Matté A.
      • Tomlinson G.
      • Diaz-Granados N.
      • Cooper A.
      • et al.
      Functional disability 5 Years after acute respiratory distress syndrome.
      ]. This myriad of symptoms is known as post-intensive care syndrome [
      • Needham D.M.
      • Davidson J.
      • Cohen H.
      • Hopkins R.O.
      • Weinert C.
      • Wunsch H.
      • et al.
      Improving long-term outcomes after discharge from intensive care unit.
      ]. As a consequence, ICU survivors are more likely to be readmitted to the hospital and ICU, and demand more home-care compared with non-ICU hospitalized patients [
      • Puthucheary Z.A.
      • Rawal J.
      • McPhail M.
      • Connolly B.
      • Ratnayake G.
      • Chan P.
      • et al.
      Acute skeletal muscle wasting in critical illness.
      ]. This calls for further research into the aetiology, modulating factors and possible ways for prevention or intervention of this syndrome.
      An important cause of physical weakness is the loss of muscle mass and function during critical illness [
      • Connolly B.
      • MacBean V.
      • Crowley C.
      • Lunt A.
      • Moxham J.
      • Rafferty G.F.
      • et al.
      Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness.
      ]. Interestingly, intracellular signalling patterns associated with increased muscle breakdown and decreased muscle synthesis are upregulated [
      • Puthucheary Z.A.
      • Rawal J.
      • McPhail M.
      • Connolly B.
      • Ratnayake G.
      • Chan P.
      • et al.
      Acute skeletal muscle wasting in critical illness.
      ,
      • Klaude M.
      • Mori M.
      • Tjäder I.
      • Gustafsson T.
      • Wernerman J.
      • Rooyackers O.
      Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis.
      ]. Loss of muscle mass and function has been shown to be more pronounced in patients with multi-organ failure compared with patients with single organ failure, indicating that it is related to disease severity.
      Therapeutic interventions aiming to restore or prevent loss of muscle mass and function include exercise and increase of protein intake during and shortly after critical illness. However, conflicting results regarding their benefits have been published [
      • Cawood A.L.
      • Elia M.
      • Stratton R.J.
      Systematic review and meta-analysis of the effects of high protein oral nutritional supplements.
      ,
      • Connolly B.
      • Salisbury L.
      • O'Neill B.
      • Geneen L.
      • Douiri A.
      • Grocott M.P.W.
      • et al.
      Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a Cochrane Collaboration systematic review.
      ,
      • Kayambu G.
      • Boots R.
      • Paratz J.
      Physical therapy for the critically ill in the ICU: a systematic review and meta-analysis.
      ,
      • Heyland D.K.
      • Rooyakers O.
      • Mourtzakis M.
      • Stapleton R.D.
      Proceedings of the 2016 clinical nutrition week research workshop—the optimal dose of protein provided to critically ill patients.
      ].
      Recently, the attention has shifted towards persistent mitochondrial dysfunction as a critical factor [
      • Batt J.
      • Mathur S.
      • Katzberg H.D.
      Mechanism of ICU-acquired weakness: muscle contractility in critical illness.
      ], since the majority of patients show a reduced ability to produce ATP, which is called bio-energetic failure [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ] (Fig. 1). Interestingly, restoring mitochondrial bio-energetic functions has been shown to increase muscle force in septic mice [
      • Rocheteau P.
      • Chatre L.
      • Briand D.
      • Mebarki M.
      • Jouvion G.
      • Bardon J.
      • et al.
      Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.
      ], and up-regulation of genes involved in mitochondrial biogenesis was associated with survival [
      • Carré J.E.
      • Orban J.-C.
      • Re L.
      • Felsmann K.
      • Iffert W.
      • Bauer M.
      • et al.
      Survival in critical illness is associated with early activation of mitochondrial biogenesis.
      ]. It is well established that for optimal function mitochondria require a range of co-factors, including many micronutrients. To further explore this, we aimed to 1) assess the scientific literature on mitochondrial dysfunction during and after critical illness, and 2) describe potential roles of specific micro-nutritional components in preventing or restoring mitochondrial damage resulting from critical illness.
      Fig. 1
      Fig. 1Factors affecting mitochondrial function during and after critical illness. Mitochondrial function is essential to survive critical illness. Several factors are associated with mitochondrial dysfunction. Mitochondrial dysfunction is associated with decreased energy production reflected by lower ATP availability and increased lactate levels. Adequate nutrition during and after critical illness may improve mitochondrial function and result in better long-term physical and neurocognitive outcomes after critical illness. ATP: adenosinetriphosphate; GI-tract: Gastro-intestinal tract.

      2. Mitochondrial bio-energetics

      The primary function of mitochondria is to supply cellular energy by producing adenosine triphosphate (ATP) (Fig. 2).
      Fig. 2
      Fig. 2Mitochondrial energy production. The oxidative phosphorylation (OXPHOS) system consists of five mitochondrial complexes and provides cellular energy by generating adenosinetriphospate (ATP) from adenosinediphosphate (ADP). The electron transport chain consists of the first four mitochondrial complexes. NADH and FADH2 are used as electron donors by the first and second complex. Mitochondria depend on the availability of reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are generated during the utilization of glucose, fatty acids and, to a lesser extent, amino acids
      [
      • Batt J.
      • Mathur S.
      • Katzberg H.D.
      Mechanism of ICU-acquired weakness: muscle contractility in critical illness.
      ]
      . The energy released during the electron transfer through the electron transport chain is used to pump protons (H+) in the mitochondrial matrix over the inner mitochondrial membrane into the intermembrane space. This process generates a proton gradient across this membrane. The energy stored in this proton gradient is used by THE FOF1-ATPase (complex V), which together with the electron transport chain forms the OXPHOS system, to generate ATP from ADP and inorganic phosphate
      [
      • Batt J.
      • Mathur S.
      • Katzberg H.D.
      Mechanism of ICU-acquired weakness: muscle contractility in critical illness.
      ]
      .
      Apart from energy metabolism, mitochondria also play essential roles in cell signalling, cellular differentiation, and cell death, as well as control of the cell cycle and cell growth [
      • Harrois A.
      • Huet O.
      • Duranteau J.
      Alterations of mitochondrial function in sepsis and critical illness.
      ].
      Bio-energetic failure of skeletal muscle is suggested to be associated with ICU-acquired weakness [
      • Batt J.
      • Mathur S.
      • Katzberg H.D.
      Mechanism of ICU-acquired weakness: muscle contractility in critical illness.
      ]. The OXPHOS system, essential for ATP production, has been shown to be affected in muscles of critically ill patients [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      ,
      • Frederiksson K.
      • Fläring U.
      • Guillet C.
      • Wernerman J.
      • Rooyackers
      Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ,
      • Fredriksson K.
      • Tjäder I.
      • Keller P.
      • Petrovic N.
      • Ahlman B.
      • Schéele C.
      • et al.
      Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure.
      ] (summarized in Table 1). ATP production is significantly decreased during critical illness [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ], and even more profoundly in non-survivors [
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      ]. Accordingly, the activity of several complexes involved (Fig. 2) has also been found to be decreased. Specifically, the activity of complex I [
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ,
      • Fredriksson K.
      • Tjäder I.
      • Keller P.
      • Petrovic N.
      • Ahlman B.
      • Schéele C.
      • et al.
      Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure.
      ], III [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ], and IV [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ,
      • Fredriksson K.
      • Tjäder I.
      • Keller P.
      • Petrovic N.
      • Ahlman B.
      • Schéele C.
      • et al.
      Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure.
      ] expressed per mg muscle wet weight was significantly decreased in critically ill patients compared with controls. The activity of complexes I [
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ] was even more decreased in non-survivors. Contrary to these results, when normalized on citrate synthase activity, which is often used as a marker for mitochondrial content, the activities of complex I, and IV did not differ in critically ill patients compared to controls [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      • Frederiksson K.
      • Fläring U.
      • Guillet C.
      • Wernerman J.
      • Rooyackers
      Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ]. Also increased activity of complex II and III in critically ill patients [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ] and of complex IV in non-survivors compared with survivors was reported [
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ]. Caution should be taken when data is normalized on citrate synthase, because its activity itself may change as a consequence of disease or treatment [
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      • Frederiksson K.
      • Fläring U.
      • Guillet C.
      • Wernerman J.
      • Rooyackers
      Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.
      ]. Moreover, citrate synthase activity is regulated by its end product, ATP, which has been shown to be reduced in critical illness, in particular in sepsis [
      • Jeger V.
      • Djafarzadeh S.
      • Jakob S.M.
      • Takala J.
      Mitochondrial function in sepsis.
      ]. Although data on the course of mitochondrial function during critical illness are lacking, results of recent studies strongly suggest that mitochondrial bio-energetic function is impaired during and after critical illness. Interestingly, 2 h after a human endotoxin challenge, in order to mimic sepsis, complex I and citrate synthase activity increased compared to controls suggesting increased mitochondrial functioning. Why and when mitochondrial function eventually decreases remains to be answered. Moreover, in survivors, mitochondrial regeneration follows damage [
      • Carré J.E.
      • Orban J.-C.
      • Re L.
      • Felsmann K.
      • Iffert W.
      • Bauer M.
      • et al.
      Survival in critical illness is associated with early activation of mitochondrial biogenesis.
      ,
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      ,
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      ,
      • Garrabou G.
      • Moren C.
      • Lopez S.
      • Tobias E.
      • Cardellach F.
      • Miro O.
      • et al.
      The effects of sepsis on mitochondria.
      ], underlining that proper mitochondrial functioning is essential for survival.
      Table 1Studies assessing mitochondrial function in critically ill patients.
      AuthorYearStudy populationDesignSamplesMethodsOutcomesMain results
      Brealey et al.,
      • Brealey D.
      • Brand M.
      • Hargreaves I.
      • Heales S.
      • Land J.
      • Smolenski R.
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      200228 ICU patients and 9 control patients (hip surgery)Cross-sectionalMuscle biopsy within 24 h of ICU admissionMitochondrial complex activities were measured by spectrophotometry,

      Adjusted for citrate synthase activity. ATP, ADP and AMP were measured by reverse-phase high-performance liquid chromatography.
      Skeletal muscle mass ATP concentrationsMuscle ATP concentrations were significantly lower in the 12 septic patients who died compared with those (16) who survived (7.6 nmoL/mg dry weight vs 15.8; p < 0.001) and controls (7.6 vs 12.5; p = 0.05). Increased complex I activity was associated with less severe septic shock and increased concentrations of reduced glutathione and ATP.
      Fredriksson et al., 2006
      • Fredriksson K.
      • Hammarqvist F.
      • Strigård K.
      • Hultenby K.
      • Ljungqvist O.
      • Wernerman J.
      • et al.
      Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure.
      10 ICU with sepsis induced multi-organ failure and 10 metabolically healthy age- and sex-matched control patients (elective surgery)Cross-sectionalMuscle biopsies from vastus lateralis (leg) and serratus anterior muscles.Complex I and IV activity was assessed using spectrophotometric assays. ATP and creatine phosphate concentrations were measured enzymatically. The morphological evaluation was done by a trained pathologist using a Tecnai 10 electron microscope.Activity citrate synthases and complexes I and IV. Concentrations ATP, creatine phosphate and lactate. Morphology mitochondria.Lower activity of citrate synthases (53%) and complex I (60%) in rib muscle but not in leg muscle compared with controls. The activity of complex IV was 30% lower in leg muscle but not in rib muscle. Concentrations of ATP (40%) and creatine phosphate (34%) were lower and lactate concentrations 43% higher in leg muscle. Both in leg and in rib muscle a twofold decrease in mitochondrial content was found.
      Fredriksson et al.
      • Fredriksson K.
      • Tjäder I.
      • Keller P.
      • Petrovic N.
      • Ahlman B.
      • Schéele C.
      • et al.
      Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure.
      ,
      200817 ICU patients and 10 age-matched controlsCross-sectionalSkeletal muscle biopsiesActivities of citrate synthases, complex I and IV were assessed using spectrophotometry. Mitochondrial protein synthesis was assessed using gas chromatography-mass spectrometry analysis.Transcript profiling (mitochondrial genes)Muscle mitochondrial enzyme (citrate synthases, complex I and IV) activities are decreased with sepsis (−25%, −49% and −33% respectively). However, in isolated mitochondrial complex IV activity was increased in septic patients (+60%) compared to controls. Neither in vivo protein synthesis nor the expression of mitochondrial genes was compromised.
      Fredriksson et al.
      • Frederiksson K.
      • Fläring U.
      • Guillet C.
      • Wernerman J.
      • Rooyackers
      Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.
      ,
      20097 healthy male volunteers received endotoxin challengeTrialSkeletal muscle biopsies (before, 2 and 4 h after challenge).Mitochondrial citrate synthases, complexes I and IV activity were measured using spectrophotometric assays on a Konelab analyser.Maximal activities of citrate synthase and complex I and IV.Activities of citrate synthase and complex I were significantly increased 2 h after endotoxin challenge (+16% and +68% respectively). No changes in ATP, creatine phosphate or lactate.
      Jiroutkova et al.
      • Jiroutková K.
      • Krajčová A.
      • Ziak J.
      • Fric M.
      • Waldauf P.
      • Džupa V.
      • et al.
      Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.
      ,
      20158 ventilated patients with ICU-acquired weakness and 8 age and sex-matched metabolically healthy controls.Cross-sectionalMuscle biopsies (of m. vastus lateralis).Spectrophotometric analyses were used to assess the activities of the individual complexes.Activities of respiratory complexesThe ability of aerobic ATP synthesis was reduced in 54% of ICU patients. This was correlated to depletion of complexes III (38% of controls; p = 0.02) and IV (26% of controls, p < 0.01) without signs of mitochondrial uncoupling. When adjusted for citrate synthase, the activity of complexes I and IV was not different, while the activity of complexes II (3 fold) and III (3 fold) were increased in ICU patients. Non-survivors of septic shock showed a significant lower complex I and higher complex IV activity expressed per citrate synthase activity compared with survivors and healthy controls
      Notes: ATP: Adenosine triphosphate; ICU: intensive care unit.

      2.1 Substrate oxidation during critical illness

      High plasma levels of lactate and free fatty acids, hyperglycaemia and hypertriglyceridemia are indicators of major changes in intermediary metabolism in critically ill patients [
      • Wolfe R.R.
      • Martini W.Z.
      Changes in intermediary metabolism in severe surgical illness.
      ]. Under normal physiological conditions, an increase in glucose concentration stimulates insulin secretion, which in turn suppresses lipolysis and stimulates glucose uptake in different tissues, including muscle.
      However, during critical illness, this normal inverse relationship between fatty acid and glucose availability is disturbed. The stress response stimulates a more general energy mobilization involving both glucose and fatty acids simultaneously. During critical illness, the usual suppressive effects of ingested carbohydrates on hepatic glucose output are diminished, leading to hyperglycaemia [
      • Mizock B.A.
      Alterations in fuel metabolism in critical illness: hyperglycaemia.
      ]. In addition, excessive lipolysis occurs leading to high plasma free fatty acids and increased concentrations of VLDL-TG, which in turn causes an increased hepatic triglyceride production [
      • Wolfe R.R.
      • Martini W.Z.
      Changes in intermediary metabolism in severe surgical illness.
      ]. Under normal conditions, increased levels of free fatty acids would stimulate beta-oxidation. However, this response is inhibited during critical disease as the increased rate of glycolysis inhibits carnitine acyltransferase I via malonyl Co-A [
      • Wolfe R.R.
      • Martini W.Z.
      Changes in intermediary metabolism in severe surgical illness.
      ,
      • Maitra U.
      • Chang S.
      • Singh N.
      • Li L.
      Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia.
      ].
      Interestingly, this balance between energy substrates is not only disturbed during the critical stages of illness but may continue during the recovery period. For example, a recent study found that patients surviving severe burn injury showed no capacity to utilize fat for energy in the muscles months after ICU discharge, limiting exercise performance to only a few minutes [
      • Wischmeyer P.E.
      • San-Millan I.
      Winning the war against ICU-acquired weakness: new innovations in nutrition and exercise physiology.
      ].

      2.2 Factors involved in mitochondrial damage

      Originally, hypoxia was considered the leading cause of the decreased ATP production seen in critically ill patients [
      • Fink M.P.
      Cytopathic Hypoxia: mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.
      ]. However, studies in critically ill septic patients finding elevated tissue oxygen levels in combination with decreased oxygen consumption and altered microvascular flow suggest a problem in cellular respiration rather than in oxygen delivery [
      • Raffaella T.
      • Fiore F.
      • Fabrizia M.
      • Francesco P.
      • Arcangela L.
      • Salvatore S.
      • et al.
      Induction of mitochondrial dysfunction and oxidative stress in human fibroblast cultures exposed to serum from septic patients.
      ]. The fundamental failure in cellular respiration was named ‘cytopathic hypoxia' by Fink [
      • Fink M.P.
      Cytopathic Hypoxia: mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.
      ].
      An important factor involved in mitochondrial damage is oxidative stress. Under normal physiological conditions mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced [
      • Liemburg-Apers D.C.
      • Willems P.H.G.M.
      • Koopman W.J.H.
      • Grefte S.
      Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism.
      ]. A slight shift in this balance can lead to the activation of important cell signalling pathways [
      • Liemburg-Apers D.C.
      • Willems P.H.G.M.
      • Koopman W.J.H.
      • Grefte S.
      Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism.
      ]. However, oxidative stress occurs when the mitochondrial ROS production significantly exceeds the capacity of the cellular antioxidant systems [
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ]. This can cause irreversible damage to the lipid mitochondrial membrane, enzymes and mtDNA and thereby induce cell damage and death [
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ]. Oxidative stress-mediated damage to mtDNA can lead to a vicious cycle of ROS production (ROS-induced ROS release) and further mtDNA damage [
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ], ultimately leading to loss of function of enzymes in the electron transfer system and/or cell death [
      • Indo H.P.
      • Davidson M.
      • Yen H.-C.
      • Suenaga S.
      • Tomita K.
      • Nishii T.
      • et al.
      Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage.
      ]. This is known as the ‘mitochondrial catastrophe hypothesis [
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ].
      Oxidative stress in mitochondria probably decreases ATP production by direct inhibitory effects on complexes of the respiratory chain. It has been suggested that complex IV is temporarily inhibited by nitric oxide [
      • Torres J.
      • Darley-Usmar V.
      • Wilson M.T.
      Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration.
      ,
      • Carré J.E.
      • Singer M.
      Cellular energetic metabolism in sepsis: the need for a systems approach.
      ], while the inhibition of complex I is more stable and induced by peroxynitrite [
      • Carré J.E.
      • Singer M.
      Cellular energetic metabolism in sepsis: the need for a systems approach.
      ].
      Antioxidants and antioxidant enzymes reduce oxidative stress by four mechanisms, thereby limiting damage to mitochondria [
      • Fang Y.-Z.
      • Yang S.
      • Wu G.
      Free radicals, antioxidants, and nutrition.
      ]: (1)scavenging free radicals, (2)sequestration of transition metal ions into complexes, (3)repairing damage molecules and (4)breaking chain reactions initiated by free radicals, as in lipid peroxidation [
      • Rizzo A.M.
      • Berselli P.
      • Zava S.
      • Montorfano G.
      • Negroni M.
      • Corsetto P.
      • et al.
      Endogenous antioxidants and radical scavengers.
      ]. Dietary deficiencies of protein, selenium, and zinc are associated with cell injury. However, an excess of antioxidants may be harmful as well, and an overload of specific nutrients, such as iron and vitamin C, may lead to increased oxidation and cell injury [
      • Fang Y.-Z.
      • Yang S.
      • Wu G.
      Free radicals, antioxidants, and nutrition.
      ].
      In addition to oxidative stress, glucose homeostasis is also crucial for the proper functioning of mitochondria [
      • Vanhorebeek I.
      • Ellger B.
      • De Vos R.
      • Boussemaere M.
      • Debaveye Y.
      • Perre Vander S.
      • et al.
      Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness.
      ]. However, this is beyond the scope of this review.

      3. Micronutrients in mitochondrial function

      Several vitamins and (trace) minerals are essential for mitochondrial functioning, either by acting as cofactors in energy metabolism and/or by acting as antioxidants. These two functions are linked as the antioxidant function may prevent damage to enzymes involved in energy metabolism, thereby limiting the reduction in energy production [
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ]. The role of antioxidant vitamins and trace elements in critically ill patients has recently been investigated by our research group [
      • Koekkoek W.A.
      • van Zanten A.R.
      Antioxidant vitamins and trace elements in critical illness.
      ].
      The focus of the current review is to address the potential role of various nutrients, vitamins and trace elements in mitochondrial performance. It should be noted that although these specific micronutrients play important roles in mitochondrial function, the relevance in critical illness is speculative since only very few studies are conducted in critically ill patients. The next sections will elaborate on the potential roles of B vitamins, ascorbic acid, tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, taurine, lipoic acids, nitrate and resveratrol, all food components found to be involved in mitochondrial function.
      Most important properties, problems arising with deficiencies, recommended dietary allowance and when available guidelines of described nutritional components are summarized in Table 2. Figure 3 depicts an overview of relevant bioactive substances within the mitochondria with respect to energy metabolism and the respiratory chain.
      Table 2Potential relevant food component functions in energy metabolism and mitochondrial function.
      Food componentsRelevant functionsProblems in deficiencyRecommended Dietary Allowance (RDA) or adequate intake (AI)
      • Institute of Medicine (U.S.)
      Panel on Micronutrients. DRI : dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc : a report of the Panel on Micronutrients ... and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes.
      ,
      • Institute of Medicine (US)
      Standing committee on the scientific evaluation of dietary reference intakes and its panel on folate, other B vitamins and C. Dietary reference intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, VItamin B12, Panthothenic Acid, Biotin, and Choline.
      ,
      • National Research Council (U.S.), Institute of Medicine (U.S.)
      Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids : a report of the panel on dietary antioxidants and related compounds, subcommittees on upper reference levels of nutrients and of interpretation and use of dietary reference intakes, and the standing committee on the scientific evaluation of dietary reference intakes.
      Remarks
      Water-soluble vitamins
      Thiamin (vitamin B1)

      Active form thiamine pyrophosphate
      Cofactor for cytosolic transketolase and PDH

      Cofactor for mitochondrial α-KGDH and branched-chain ketoacid dehydrogenase
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      Impaired aerobic metabolism due to a reduced ability of pyruvate to enter TCA cycle resulting in lactic acidosis
      • Donnino M.W.
      • Carney E.
      • Cocchi M.N.
      • Barbash I.
      • Chase M.
      • Joyce N.
      • et al.
      Thiamine deficiency in critically ill patients with sepsis.
      .
      >19 year Men: 1.2 mg/day Women: 1.1 mg/day
      Riboflavin (vitamin B2)Flavoprotein precursor and key building block for complexes I and II

      Involved in beta-oxidation (TCA cycle)

      The precursor of flavin adenine dinucleotide (FAD)and flavin mononucleotide (FMN)
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      FAD-dependent dehydrogenase inhibition resulting in impaired mitochondrial oxidation of fatty acids and branched amino-acids
      • Nagao M.
      • Tanaka K.
      FAD-dependent regulation of transcription, translation, post-translational processing, and post-processing stability of various mitochondrial acyl-CoA dehydrogenases and of electron transfer flavoprotein and the site of holoenzyme formation.
      .
      >19 year Men: 1.1 mg/day Women: 0.9 mg/day
      Niacin (vitamin B3)Precursor of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Involved in glycolysis and TCA cycle
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      .
      Decreased overall energy production>19 year

      Men: 16 mg/day Women: 14 mg/day
      Pantothenic acid (vitamin B5)Precursor of CoA and therefore crucial in the function of PDH and α-KGDH
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      .
      Impaired functioning of PDH and α-KGDH resulting in reduced ability to generate energy from fatty acids.>19 year

      Men: 5 mg/day Women: 5 mg/day
      Biotin (vitamin B7)Coenzyme of five mitochondrial carboxylases and essential for normal mitochondrial and cellular function.

      Essential for fatty acid oxidation and gluconeogenesis
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      .
      Impaired fatty acid oxidation and gluconeogenesis.* >19 year

      Men: 30 μg/day Women: 30 μg/day
      Folate (vitamin B9)Initiation of mitochondrial protein synthesis

      Synthesis of glycine

      Cleavage of serine to 5,10-methyltetrahydrofolate (needed for synthesis of purines and thymidylate)
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.
      .
      Decreased ATP formation and DNA synthesis
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.
      .
      >19 year

      Men: 320 μg/day of dietary folate equivalents

      Women: 400 μg/day of dietary folate equivalents
      Cobalamin (vitamin B12)

      2-deoxyadenosyl (ado) form
      Required for the synthesis of succinyl CoA from methylmalonyl-CoA

      Regulation of NF-κB, via inhibition of inducible NOS

      Antioxidant and anti-inflammatory properties

      Central role in hematopoiesis
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.
      ,
      • Drennan C.L.
      • Matthews R.G.
      • Ludwig M.L.
      Cobalamin-dependent methionine synthase: the structure of a methylcobalamin-binding fragment and implications for other B12-dependent enzymes.
      .
      Decreases ATP production and possible complex I activity.

      Impaired bacteriostasis and phagocytosis
      • Wheatley C.
      A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic or traumatic shock.
      >19 year

      Men: 2.4 μg/day

      Women: 2.4 μg/day
      Ascorbic acid (vitamin C)Antioxidant
      • Berger M.M.
      • Oudemans-van Straaten H.M.
      Vitamin C supplementation in the critically ill patient.
      , but could act as pro-oxidant in high concentrations
      • Childs A.
      • Jacobs C.
      • Kaminski T.
      • Halliwell B.
      • Leeuwenburgh C.
      Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.
      .

      Involved in the biosynthesis of carnitine, the key factor in beta-oxidation
      • Rebouche C.J.
      Ascorbic acid and carnitine biosynthesis.
      .

      Cofactor for the synthesis of catecholamines, which in turn stimulate the oxidation of carbohydrates to generate energy
      • Rochette L.
      • Ghibu S.
      • Richard C.
      • Zeller M.
      • Cottin Y.
      • Vergely C.
      Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential.
      Impaired beta-oxidation, impaired ATP production>19 years

      Men: 90 mg/day

      Women: 75 mg/day
      Fat-soluble vitamins
      Tocopherol (vitamin E)

      Bioactive form α-tocopherol
      Vitamin E is the most important lipid-soluble antioxidant in cell membranes
      • Al-Shmgani H.S.
      • Moate R.M.
      • Macnaughton P.D.
      • Sneyd J.R.
      • Moody A.J.
      Effects of hyperoxia on the permeability of 16HBE14o- cell monolayers - the protective role of antioxidant vitamins E and C.
      ,
      • Lassnigg A.
      • Punz A.
      • Barker R.
      • Keznickl P.
      • Manhart N.
      • Roth E.
      • et al.
      Influence of intravenous vitamin E supplementation in cardiac surgery on oxidative stress: a double-blinded, randomized, controlled study.
      ,
      • Crimi E.
      • Liguori A.
      • Condorelli M.
      • Cioffi M.
      • Astuto M.
      • Bontempo P.
      • et al.
      The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial.
      .

      Oxidized TQ cause a down-regulation of respiratory activity

      Essential cofactor in desaturation of saturated fatty acids
      • Infante J.P.
      A function for the vitamin E metabolite α-tocopherol quinone as an essential enzyme cofactor for the mitochondrial fatty acid desaturases.
      .
      TQ arising from excessive oxidative degradation of tocopherol can interfere with complex I, II and III activity
      • Gille L.
      • Gregor W.
      • Staniek K.
      • Nohl H.
      Redox-interaction of α-tocopheryl quinone with isolated mitochondrial cytochrome bc1 complex.
      .
      >19 years

      Men: 15 mg/day

      Women: 15 mg/day
      Trace elements
      SeleniumInvolved in mitochondrial biogenesis; stimulate PGC-1α and NRF-1

      Antioxidant (glutathione peroxidase, glutathione reductase)
      • Koekkoek W.A.
      • van Zanten A.R.
      Antioxidant vitamins and trace elements in critical illness.
      ,
      • Burk R.F.
      Selenium, an antioxidant nutrient.
      .

      Attenuate ischemia-activated autophagy
      • Mendelev N.
      • Mehta S.L.
      • Idris H.
      • Kumari S.
      • Li P.A.
      Selenite Stimulates Mitochondrial Biogenesis Signaling and Enhances Mitochondrial Functional Performance in Murine Hippocampal Neuronal Cells.
      ,
      • Yeo J.E.
      • Kim J.H.
      • Kang S.K.
      • Li P.A.
      • Gil L.
      • Elazar Z.
      • et al.
      Selenium attenuates ROS-mediated apoptotic cell death of injured spinal cord through prevention of mitochondria dysfunction; in vitro and in vivo study.
      .
      Impaired mitochondrial biogenesis>19 years

      Men: 55 μg/day

      Women: 55 μg/day
      The Canadian Clinical Practise Guidelines at present have advised against high dose selenium supplementation, as the evidence is overall inconclusive
      • Jin J.
      • Mulesa L.
      • Carrilero Rouillet M.
      Trace elements in parenteral nutrition: considerations for the prescribing clinician.
      ZincHigh levels can inhibit glycolysis and the TCA cycle
      • Bernsen P.L.J.A.
      • Gabreëls F.J.M.
      • Ruitenbeek W.
      • Hamburger H.L.
      Treatment of complex I deficiency with riboflavin.


      Antioxidant
      • Heyland D.K.
      • Jones N.
      • Cvijanovich N.Z.
      • Wong H.
      Zinc supplementation in critically ill patients: a key pharmaconutrient?.


      Important in DNA synthesis, cell proliferation, protein synthesis and cell membrane integrity
      • Koekkoek W.A.
      • van Zanten A.R.
      Antioxidant vitamins and trace elements in critical illness.
      Inhibition of glycolysis by Zn occurs by negatively affecting important enzymes such as glyceraldehydes-3-phosphate dehydrogenase and phosphofructokinase
      • Krotkiewska B.
      • Banas T.
      Interaction of Zn2+, and Cu2+, Ions with glyceraldehyde-3-phosphate dehydrogenase from bovine heart and rabbit muscle.
      . High levels of zinc inhibit α-KGDH
      • Brown A.M.
      • Kristal B.S.
      • Effron M.S.
      • Shestopalov A.I.
      • Ullucci P.A.
      • Sheu K.F.
      • et al.
      Zn2+ inhibits alpha-ketoglutarate-stimulated mitochondrial respiration and the isolated alpha-ketoglutarate dehydrogenase complex.
      and several other enzymes
      • Gazaryan I.G.
      • Krasinskaya I.P.
      • Kristal B.S.
      • Brown A.M.
      Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition.
      ,
      • Lemire J.
      • Mailloux R.
      • Appanna V.D.
      Zinc toxicity alters mitochondrial metabolism and leads to decreased ATP production in hepatocytes.
      leading to decreased ATP production
      • Lemire J.
      • Mailloux R.
      • Appanna V.D.
      Zinc toxicity alters mitochondrial metabolism and leads to decreased ATP production in hepatocytes.
      .
      >19 years

      Men: 11 mg/day

      Women: 8 mg/day
      Bioactive substances
      Coenzyme Q10Electron acceptor complex I and II
      • Lenaz G.
      • Fato R.
      • Formiggini G.
      • Genova M.L.
      The role of Coenzyme Q in mitochondrial electron transport.


      Antioxidant
      • Crane F.L.
      Biochemical functions of coenzyme Q10.
      Impaired activity complex I and II resulting in decreased ATP productionNot applicable
      CaffeineInhibit cyclic adenosine monophosphate (cAMP)-phosphodiesterase. This inhibition leads to increased levels of cAMP and the activation of protein kinase A
      • Horrigan L.A.
      • Kelly J.P.
      • Connor T.J.
      Immunomodulatory effects of caffeine: friend or foe?.
      .

      Increases cAMP resulting in increased effectiveness of complexes I and IV
      • Kadenbach B.
      Intrinsic and extrinsic uncoupling of oxidative phosphorylation.
      .
      Decreased ATP production due to impaired functioning of complexes I and IV.Not applicable
      MelatoninSleep regulation

      Antioxidant
      • Acuna-Castroviejo D.
      • Escames G.
      • Rodriguez M.I.
      • Lopez L.C.
      Melatonin role in the mitochondrial function.
      can inhibit the activity of mitochondrial nitric oxide synthase, which is assumed to play a pivotal role in sepsis
      • Escames G.
      • Lopez L.C.
      • Tapias V.
      • Utrilla P.
      • Reiter R.J.
      • Hitos A.B.
      • et al.
      Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice.


      Stimulates complexes I and IV, probably by scavenging of ROS, especially peroxynitrite and nitric oxide
      • Acuna-Castroviejo D.
      • Escames G.
      • Rodriguez M.I.
      • Lopez L.C.
      Melatonin role in the mitochondrial function.
      ,
      • Leon J.
      • Acuna-Castroviejo D.
      • Escames G.
      • Tan D.-X.
      • Reiter R.J.
      Melatonin mitigates mitochondrial malfunction.
      ,
      • Martin M.
      • Macias M.
      • Escames G.
      • Reiter R.J.
      • Agapito M.T.
      • Ortiz G.G.
      • et al.
      Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo.
      .
      Decreased ATP production due to impaired functioning of complexes I and IV.Not applicable
      CarnitineTransport of long-chain fatty acids through the mitochondrial membrane wherein these substrates undergo β oxidation

      Stimulates PDH and the TCA cycle

      Maintaining CoA pool
      Carnitine depletion could result in impaired beta-oxidation, which results in acyl-CoA accumulation and depletion of CoA pool, in turn, resulting in mitochondrial dysfunction, reduced ATP production and increased oxidative stress
      • Bonafe L.
      • Berger M.M.
      • Que Y.A.
      • Mechanick J.I.
      Carnitine deficiency in chronic critical illness.
      .
      Not applicable
      Creatine/creatine phosphateImportant temporal and spatial energy source.Hypophosphatemia results in impaired cellular energy stores, due to depletion of cellular ATP, which in turn result in neuromuscular abnormalities and mitochondrial dysfunction
      • Sarma S.
      • Gheorghiade M.
      Nutritional assessment and support of the patient with acute heart failure.
      .
      Not applicableSerum phosphate levels are carefully monitored in critically ill patients and repleted with intravenous and/or enteral phosphate.
      NitratePartial inhibition of mitochondrial respiration, due to binding to complex IV
      • Torres J.
      • Darley-Usmar V.
      • Wilson M.T.
      Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration.
      ,
      • Carré J.E.
      • Singer M.
      Cellular energetic metabolism in sepsis: the need for a systems approach.


      Stimulates mitochondrial biogenesis depending on guanosine 3,5 monophosphate, mediated by the induction of PGC-1α
      • Nisoli E.
      • Clementi E.
      • Paolucci C.
      • Cozzi V.
      • Tonello C.
      • Sciorati C.
      • et al.
      Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide.
      .

      May regulate tissue protein expression and activation, independently of NO formation
      • Bryan N.S.
      • Fernandez B.O.
      • Bauer S.M.
      • Garcia-Saura M.F.
      • Milsom A.B.
      • Rassaf T.
      • et al.
      Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues.
      .
      Lower ATP production rate and decreased mitochondrial efficiency.Not applicable
      Lipoic acidAntioxidant
      • Rochette L.
      • Ghibu S.
      • Richard C.
      • Zeller M.
      • Cottin Y.
      • Vergely C.
      Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential.
      .

      Involved in energy production as it is an essential cofactor in mitochondrial dehydrogenase complexes
      • Liu J.
      The effects and mechanisms of mitochondrial nutrient α-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview.


      Improves mitochondrial function and insulin sensitivity by activation AMPK and PGC-1α
      • Lee W.J.
      • Song K.-H.
      • Koh E.H.
      • Won J.C.
      • Kim H.S.
      • Park H.-S.
      • et al.
      α-Lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle.
      ,
      • Wang Y.
      • Li X.
      • Guo Y.
      • Chan L.
      • Guan X.
      α-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate–activated protein kinase–peroxisome proliferator-activated receptor-γ coactivator-1α signaling in the skeletal muscle of aged mice.
      .
      Decreased ATP production.Not applicable
      TaurineRole in mitochondrial protein translation.

      Induce phosphorylation of PDH
      • Bryan N.S.
      • Fernandez B.O.
      • Bauer S.M.
      • Garcia-Saura M.F.
      • Milsom A.B.
      • Rassaf T.
      • et al.
      Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues.
      ,
      • Wang Y.
      • Li X.
      • Guo Y.
      • Chan L.
      • Guan X.
      α-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate–activated protein kinase–peroxisome proliferator-activated receptor-γ coactivator-1α signaling in the skeletal muscle of aged mice.
      ,
      • Lambert I.H.
      • Kristensen D.M.
      • Holm J.B.
      • Mortensen O.H.
      Physiological role of taurine--from organism to organelle.
      ,
      • Wennberg A.
      • Hyltander A.
      • Sjöberg Å.
      • Arfvidsson B.
      • Sandström R.
      • Wickström I.
      • et al.
      Prevalence of carnitine depletion in critically ill patients with undernutrition.
      ,
      • Sarma S.
      • Gheorghiade M.
      Nutritional assessment and support of the patient with acute heart failure.
      .

      Suggested to act as a pH buffer in the mitochondrial matrix to stabilize beta-oxidation of fatty acids
      • Suzuki T.
      • Suzuki T.
      • Wada T.
      • Saigo K.
      • Watanabe K.
      Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases.
      .
      The decrease in mitochondrial respiration and activity of complex I and III
      • Lambert I.H.
      • Kristensen D.M.
      • Holm J.B.
      • Mortensen O.H.
      Physiological role of taurine--from organism to organelle.
      .
      Not applicableAlthough these mechanisms would suggest potential beneficial effects of taurine supplementation, it is not taken up by muscles after oral administration, despite increased plasma concentrations
      • Spriet L.L.
      • Whitfield J.
      Taurine and skeletal muscle function.
      .
      Fig. 3
      Fig. 3Overview of relevant nutrients in bioenergetic mitochondrial processes. Several nutrients are involved in the formation of acetyl CoA, which is essential in energy production as it is the starting point of the TCA cycle. Thiamine (vitamin B1) is essential for the conversion of pyruvate to acetyl-coA. Furthermore, high levels of zinc were found to inhibit the glycolysis and TCA cycle. Carnitine is essential in βeta-oxidation of free fatty acids. In addition to the formation of acetyl CoA, several nutrients have an direct effect on the TCA cycle. Pantothenic acid (vitamin B5) is the precursor of CoA. Vitamin B 12 is an essential cofactor in the formation of succinyl-CoA, an important metabolite of the TCA cycle. Besides, several nutrients influences the activity of the electron transport chain. Niacin (vitamin B3) is the precursor of NAD+, which has a crucial role in the formation of NADH, which on turn plays a crucial role in the electron transport chain. Complex I and IV activity is decreased during critical illness, but several nutrients positively affect complex I and IV performance. Complex I and IV may be stimulated by selenium, caffeine and melatonin. Complex I and II are also stimulated by CoQ10. Taurine depletion is associated with impaired activity of complexes I and III. Whether the effect of vitamin E on the complexes I and IV is stimulating or inhibiting has not yet been revealed. Nitrate probably inhibits complex IV activity. Riboflavin (vitamin B2) is an important building block for complexes I and II and involved in fatty acid oxidation in the TCA cycle. α-KGDH: alpha-ketoglutarate dehydrogenase; ATP: adenosine triphosphate; CoA: coenzyme A; CO2: carbon dioxide; CoQ: coenzyme Q; NAD(H): Nicotinamide adenine dinucleotide (reduced); PDH: pyruvate dehydrogenase; Vit: vitamin.

      3.1 B vitamins

      3.1.1 Thiamine (vitamin B1)

      Thiamine deficiency is common in critically ill patients (10–30%) [
      • Donnino M.W.
      • Carney E.
      • Cocchi M.N.
      • Barbash I.
      • Chase M.
      • Joyce N.
      • et al.
      Thiamine deficiency in critically ill patients with sepsis.
      ,
      • Berger M.M.
      • Shenkin A.
      • Revelly J.-P.
      • Roberts E.
      • Cayeux M.C.
      • Baines M.
      • et al.
      Copper, selenium, zinc, and thiamine balances during continuous venovenous hemodiafiltration in critically ill patients.
      ,
      • Cruickshank A.M.
      • Telfer A.B.M.
      • Shenkin A.
      Thiamine deficiency in the critically ill.
      ,
      • Donnino Michael W.
      • Cocchi Michael N.
      • Smithline Howard
      • Carney Erin
      • Chou Peter P.
      • Salciccoli J.
      Coronary artery bypass graft surgery depletes plasma thiamine levels.
      ,
      • Lima L.F.
      • Leite H.P.
      • Taddei J.A.
      Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance.
      ,
      • Manzanares W.
      • Hardy G.
      Thiamine supplementation in the critically ill.
      ,
      • Seear M.
      • Lockitch G.
      • Jacobson B.
      • Quigley G.
      • MacNab A.
      Thiamine, riboflavin, and pyridoxine deficiencies in a population of critically ill children.
      ]. Low serum thiamine levels in critically ill patients were found to be associated with worse outcome and increased mortality [
      • Lima L.F.
      • Leite H.P.
      • Taddei J.A.
      Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance.
      ,
      • Sriram K.
      • Manzanares W.
      • Joseph K.
      Thiamine in nutrition therapy.
      ]. However, a recent prospective study in 108 patients did not find an association between serum thiamine levels and mortality [
      • Costa N.A.
      • Gut A.L.
      • de Souza Dorna M.
      • Pimentel J.A.C.
      • Cozzolino S.M.F.
      • Azevedo P.S.
      • et al.
      Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock.
      ]. Although Marik and co-workers did not study mitochondrial function, they showed in a retrospective before-after clinical study among consecutive septic patients that patients treated with intravenous vitamin C, hydrocortisone, and thiamine had markedly lower mortality rates (propensity-adjusted odds of mortality 0.13 (95% CI, 0.04–0.48) [
      • Marik P.E.
      • Khangoora V.
      • Rivera R.
      • Hooper M.H.
      • Catravas J.
      Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.
      ].
      Only a few studies examined the effect of thiamine supplementation on mitochondrial function [
      • Luger M.
      • Hiesmayr M.
      • Köppel P.
      • Sima B.
      • Ranz I.
      • Weiss C.
      • et al.
      Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery.
      ,
      • Falder S.
      • Silla R.
      • Phillips M.
      • Rea S.
      • Gurfinkel R.
      • Baur E.
      • et al.
      Thiamine supplementation increases serum thiamine and reduces pyruvate and lactate levels in burn patients.
      ,
      • Donnino M.W.
      • Andersen L.W.
      • Chase M.
      • Berg K.M.
      • Tidswell M.
      • Giberson T.
      • et al.
      Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock.
      ]. A recent study found significantly lower lactate levels in patients with thiamine deficiencies after supplementation with thiamine (200 mg). Moreover, a lower mortality rate was found in thiamine-deficient patients receiving thiamine supplementation compared with placebo. However, these effects were not found in the total study population [
      • Donnino M.W.
      • Andersen L.W.
      • Chase M.
      • Berg K.M.
      • Tidswell M.
      • Giberson T.
      • et al.
      Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock.
      ]. In addition, in 20 burn patients an association between serum thiamine levels and lactate levels (r = 0.016; p = 0.002) was demonstrated [
      • Falder S.
      • Silla R.
      • Phillips M.
      • Rea S.
      • Gurfinkel R.
      • Baur E.
      • et al.
      Thiamine supplementation increases serum thiamine and reduces pyruvate and lactate levels in burn patients.
      ]. On the contrary, thiamine supplementation (300 mg) before cardiac surgery did not significantly reduce lactate concentrations in a pilot study among 30 patients [
      • Luger M.
      • Hiesmayr M.
      • Köppel P.
      • Sima B.
      • Ranz I.
      • Weiss C.
      • et al.
      Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery.
      ].

      3.1.2 Riboflavin (vitamin B2)

      Levels of riboflavin have barely been studied during critical illness. Shenkin and colleagues found an association between lower riboflavin levels and a higher mortality in 152 critically ill patients [
      • Shenkin S.D.
      • Cruickshank A.M.
      • Shenkin A.
      Subclinical riboflavin deficiency is associated with outcome of seriously ill patients.
      ]. In a study with 80 critically ill children, where the elevation of glutathione reductase was used as an indicator for riboflavin deficiency, 3.8% was deficient [
      • Seear M.
      • Lockitch G.
      • Jacobson B.
      • Quigley G.
      • MacNab A.
      Thiamine, riboflavin, and pyridoxine deficiencies in a population of critically ill children.
      ]. By contrast, another study in 125 critically ill patients and 119 healthy controls showed significantly elevated plasma riboflavin and flavin mononucleotide concentrations and significantly reduced concentrations of FAD among critically ill patients. In addition, the ratio of plasma FAD to riboflavin was much lower in critically ill patients compared with controls. These results indicate disturbances in plasma FAD and riboflavin metabolism [
      • Vasilaki A.T.
      • McMillan D.C.
      • Kinsella J.
      • Duncan A.
      • O'Reilly D.S.J.
      • Talwar D.
      Relation between riboflavin, flavin mononucleotide and flavin adenine dinucleotide concentrations in plasma and red cells in patients with critical illness.
      ]. A small study in 4 patients with mitochondrial myopathy, associated with complex I deficiency, showed normalization of complex I activity after treatment with riboflavin [
      • Bernsen P.L.J.A.
      • Gabreëls F.J.M.
      • Ruitenbeek W.
      • Hamburger H.L.
      Treatment of complex I deficiency with riboflavin.
      ].

      3.1.3 Cobalamin (vitamin B12)

      Vitamin B12 levels in a normal range (191–663 pg/mL) [
      • Kutlucan L.
      • Kutlucan A.
      • Basaran B.
      • Dagli M.
      • Basturk A.
      • Kozanhan B.
      • et al.
      The predictive effect of initial complete blood count of intensive care unit patients on mortality, length of hospitalization, and nosocomial infections.
      ] are essential during critical illness. Remarkably, data on the associations between plasma vitamin B12 levels, disease severity, and outcome appear to be non-consistent. Both deficiencies, but also elevated levels have been found to be associated with adverse effects. Critically ill patients have been found to be at risk of cobalamin deficiency, especially those patients suffering from burns and severe trauma, elderly, patients receiving chronic renal replacement therapy, patients who underwent gastric surgery or are suffering from bowel disorders [
      • Manzanares W.
      • Hardy G.
      Vitamin B12: the forgotten micronutrient for critical care.
      ]. Vitamin B12 deficiency is associated with megaloblastic anaemia and demyelinating neurological diseases [
      • Stabler S.P.
      Vitamin B12 deficiency.
      ]. At the same time, other studies have reported two-fold higher vitamin B12 levels in non-survivors compared with survivors [
      • Kutlucan L.
      • Kutlucan A.
      • Basaran B.
      • Dagli M.
      • Basturk A.
      • Kozanhan B.
      • et al.
      The predictive effect of initial complete blood count of intensive care unit patients on mortality, length of hospitalization, and nosocomial infections.
      ,
      • Sviri S.
      • Khalaila R.
      • Daher S.
      • Bayya A.
      • Linton D.M.
      • Stav I.
      • et al.
      Increased Vitamin B12 levels are associated with mortality in critically ill medical patients.
      ]. Even after adjustment for APACHE score, age, chronic diseases, sepsis and ventilation, elevated vitamin B12 levels remained associated with higher mortality [
      • Sviri S.
      • Khalaila R.
      • Daher S.
      • Bayya A.
      • Linton D.M.
      • Stav I.
      • et al.
      Increased Vitamin B12 levels are associated with mortality in critically ill medical patients.
      ]. Yet another study found no association between high vitamin B12 levels and mortality risk after adjusting for liver functions [
      • Callaghan F.M.
      • Leishear K.
      • Abhyankar S.
      • Demner-Fushman D.
      • McDonald C.J.
      High vitamin B12 levels are not associated with increased mortality risk for ICU patients after adjusting for liver function: a cohort study.
      ]. To our knowledge, there are no published studies assessing the effect of vitamin B12 on mitochondrial function specifically in ICU patients.

      3.1.4 Other B vitamins

      The role of niacin, pantothenic acid, biotin and folate in mitochondrial function and energy metabolism has been described in detail previously [
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
      ,
      • Depeint F.
      • Bruce W.R.
      • Mehta R.
      • O'Brien P.J.
      Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.
      ]. To our knowledge, no studies have been performed in critically ill patients assessing the status of these B vitamins and their associations with clinical outcomes and/or mitochondrial function.

      3.2 Ascorbic acid (vitamin C)

      Levels of vitamin C are significantly lower in critically ill patients compared with healthy controls [
      • Metnitz P.G.H.
      • Bartens C.
      • Fischer M.
      • Fridrich P.
      • Steltzer H.
      • Druml W.
      Antioxidant status in patients with acute respiratory distress syndrome.
      ,
      • Borrelli Emma
      • Roux-Lombard Pascale
      • Grau Georges E.
      • Girardin Eric
      • Ricou Bara
      • Dayer J.M.
      • et al.
      Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk.
      ,
      • Schorah C.J.
      • Downing C.
      • Piripitsi A.
      • Gallivan L.
      • Al-Hazaa A.H.
      • Sanderson M.J.
      • et al.
      Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients.
      ]. In addition, vitamin C deficiency is associated with increased risk of mortality. Several trials found a positive effect of vitamin C supplementation on clinical outcomes, including ICU and hospital length of stay [
      • Bjordahl P.M.
      • Helmer S.D.
      • Gosnell D.J.
      • Wemmer G.E.
      • O'Hara W.W.
      • Milfeld D.J.
      Perioperative supplementation with ascorbic acid does not prevent atrial fibrillation in coronary artery bypass graft patients.
      ,
      • Sadeghpour A.
      • Alizadehasl A.
      • Kyavar M.
      • Sadeghi T.
      • Moludi J.
      • Gholizadeh F.
      • et al.
      Impact of vitamin C supplementation on post-cardiac surgery ICU and hospital length of stay.
      ], as well as mortality [
      • Fowler A.A.
      • Syed A.A.
      • Knowlson S.
      • Sculthorpe R.
      • Farthing D.
      • DeWilde C.
      • et al.
      Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.
      ].
      Castro and colleagues found inhibition of glucose transport and activation of lactate transport with high intracellular ascorbic acid in neurons expressing the GLUT1, GLUT3, sodium vitamin C transporters and monocarboxylate transporters [
      • Castro M.A.
      • Angulo C.
      • Brauchi S.
      • Nualart F.
      • Concha I.I.
      Ascorbic acid participates in a general mechanism for concerted glucose transport inhibition and lactate transport stimulation.
      ]. The clinical consequences of these vitamin C-associated alterations in carbohydrate metabolism have not been determined yet. To our knowledge, no studies have been published assessing the effects of vitamin C on mitochondrial function in critically ill patients. Effects of vitamin C administration on muscle energy metabolism have been studied in athletes [
      • Gomez-Cabrera M.-C.
      • Domenech E.
      • Romagnoli M.
      • Arduini A.
      • Borras C.
      • Pallardo F.V.
      • et al.
      Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance.
      ,
      • Paulsen G.
      • Cumming K.T.
      • Holden G.
      • Hallén J.
      • Rønnestad B.R.
      • Sveen O.
      • et al.
      Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial.
      ], who may take vitamin C supplements to limit oxidative stress related to intense exercise. Remarkably, vitamin C supplementation was found to decrease cellular adaptations to exercise, by hampering mitochondrial biogenesis via a reduction of the expression of PGC1α, NRF1, and Tfam. In addition, vitamin C prevented the exercise-induced expression of cytochrome C (part of complex IV) [
      • Gomez-Cabrera M.-C.
      • Domenech E.
      • Romagnoli M.
      • Arduini A.
      • Borras C.
      • Pallardo F.V.
      • et al.
      Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance.
      ,
      • Paulsen G.
      • Cumming K.T.
      • Holden G.
      • Hallén J.
      • Rønnestad B.R.
      • Sveen O.
      • et al.
      Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial.
      ]. Furthermore, the increase in the maximal rate of oxygen consumption was lower in athletes who received vitamin C supplements compared with the non-supplemented controls [
      • Gomez-Cabrera M.-C.
      • Domenech E.
      • Romagnoli M.
      • Arduini A.
      • Borras C.
      • Pallardo F.V.
      • et al.
      Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance.
      ].

      3.3 Tocopherol (vitamin E)

      A study in rats showed that a mitochondrial targeted vitamin E compound (Mito-Vit-E) was able to increase complex IV activity in the liver of septic rats compared with control rats [
      • Lowes D.A.
      • Webster N.R.
      • Murphy M.P.
      • Galley H.F.
      Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis.
      ]. Furthermore, Mito-Vit-E protected mitochondrial structure and function in heart cells by maintaining mitochondrial membrane integrity, recovery of respiratory function and reduction of lipid and protein oxidation [
      • Zang Q.S.
      • Sadek H.
      • Maass D.L.
      • Martinez B.
      • Ma L.
      • Kilgore J.A.
      • et al.
      Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.
      ].
      To our knowledge, no studies were performed on critically ill patients assessing the effect of vitamin E on mitochondrial function.

      3.4 Selenium

      Results from in-vitro studies in hippocampal neuronal cells have suggested that pre-treatment with Se limits the effect of hypoxia on mitochondrial complexes by normalizing complex I and IV levels and significantly improving complex II and III activity compared with non-Se treated cells. These effects may be associated with modulation of Akt and cAMP response element binding. Selenium availability changes during critical illness. During systemic inflammation, selenium and other vitamins and minerals are redistributed to tissues involved in protein synthesis and immune cell proliferation [
      • Hardy G.
      • Hardy I.
      • Manzanares W.
      Selenium supplementation in the critically ill.
      ]. Several studies indicate that Se status is associated with clinical outcome [
      • Forceville X.
      • Vitoux D.
      • Gauzit R.
      • Combes A.
      • Lahilaire P.
      • Chappuis P.P.
      Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.
      ,
      • Sakr Y.
      • Reinhart K.
      • Bloos F.
      • Marx G.
      • Russwurm S.
      • Bauer M.
      • et al.
      Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure.
      ,
      • Manzanares W.
      • Biestro A.
      • Galusso F.
      • Torre M.H.
      • Mañay N.
      • Pittini G.
      • et al.
      Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill?.
      ,
      • Stoppe C.
      • Schälte G.
      • Rossaint R.
      • Coburn M.
      • Graf B.
      • Spillner J.
      • et al.
      The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients*.
      ]. These studies found that Se levels were lower in critically ill patients compared with healthy controls and that Se levels decrease during critical illness. In addition, low Se concentrations were associated with worse clinical outcomes such as new organ failure and mortality [
      • Forceville X.
      • Vitoux D.
      • Gauzit R.
      • Combes A.
      • Lahilaire P.
      • Chappuis P.P.
      Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.
      ,
      • Manzanares W.
      • Biestro A.
      • Galusso F.
      • Torre M.H.
      • Mañay N.
      • Pittini G.
      • et al.
      Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill?.
      ,
      • Stoppe C.
      • Schälte G.
      • Rossaint R.
      • Coburn M.
      • Graf B.
      • Spillner J.
      • et al.
      The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients*.
      ]. Furthermore, non-survivors had lower levels of Se at ICU admission and subsequent ICU stay [
      • Sakr Y.
      • Reinhart K.
      • Bloos F.
      • Marx G.
      • Russwurm S.
      • Bauer M.
      • et al.
      Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure.
      ].
      Many studies assessing the effect of Se on mortality in critically ill patients were done, with conflicting results [
      • Koekkoek W.A.
      • van Zanten A.R.
      Antioxidant vitamins and trace elements in critical illness.
      ]. To our knowledge, no studies assessing the effect of Se on the respiratory chain and mitochondrial function in critically ill patients have been done yet.

      3.5 Zinc

      Due to alterations in zinc disposition during the systemic inflammatory response, it is difficult to diagnose true zinc deficiency. Lower zinc plasma levels were associated with higher diseases severity. However, no differences in zinc levels were found between survivors and non-survivors [
      • Duncan A.
      • Dean P.
      • Simm M.
      • O'Reilly D.S.
      • Kinsella J.
      Zinc supplementation in intensive care: results of a UK survey.
      ,
      • Linko R.
      • Karlsson S.
      • Pettilä V.
      • Varpula T.
      • Okkonen M.
      • Lund V.
      • et al.
      Serum zinc in critically ill adult patients with acute respiratory failure.
      ,
      • Besecker B.Y.
      • Exline M.C.
      • Hollyfield J.
      • Phillips G.
      • DiSilvestro R.A.
      • Wewers M.D.
      • et al.
      A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission.
      ,
      • Cander B.
      • Dundar Z.D.
      • Gul M.
      • Girisgin S.
      Prognostic value of serum zinc levels in critically ill patients.
      ].
      To our knowledge, no studies assessing the effect of zinc supplementation on mitochondrial function in critically ill patients have been published.

      3.6 Coenzyme Q10

      Already decades ago it was shown that levels of CoQ10 were associated with the activity of complex I and complex II/III [
      • Shults C.W.
      • Haas R.H.
      • Passov D.
      • Beal M.F.
      Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects.
      ].
      Several studies found lower levels of CoQ10 in critically ill patients compared with healthy controls [
      • Coppadoro A.
      • Berra L.
      • Kumar A.
      • Pinciroli R.
      • Yamada M.
      • Schmidt U.H.
      • et al.
      Critical illness is associated with decreased plasma levels of coenzyme Q10: a cross-sectional study.
      ,
      • Coppadoro A.
      • Berra L.
      • Kumar A.
      • Yamada M.
      • Pinciroli R.
      • Bittner E.
      • et al.
      Plasma levels of Coenzyme Q10 are reduced in critically ill patients as compared to healthy volunteers and correlate with age.
      ,
      • Cocchi M.N.
      • Giberson B.
      • Berg K.
      • Salciccioli J.D.
      • Naini A.
      • Buettner C.
      • et al.
      Coenzyme Q10 levels are low and associated with increased mortality in post-cardiac arrest patients.
      ,
      • Donnino M.W.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Kim D.
      • Naini A.B.
      • Buettner C.
      • et al.
      Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock.
      ]. Donnino and colleagues reported significantly lower CoQ10 levels in patients with septic shock compared with healthy controls (0.49 μmoL/L vs 0.95 μmoL/L) [
      • Donnino M.W.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Kim D.
      • Naini A.B.
      • Buettner C.
      • et al.
      Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock.
      ]. In addition, lower CoQ10 levels after cardiac arrest compared with healthy controls were found (0.28 μmoL/L vs 0.75 μmoL/L). Furthermore, lower CoQ10 levels were associated with poor neurologic outcome and increased mortality risk [
      • Cocchi M.N.
      • Giberson B.
      • Berg K.
      • Salciccioli J.D.
      • Naini A.
      • Buettner C.
      • et al.
      Coenzyme Q10 levels are low and associated with increased mortality in post-cardiac arrest patients.
      ]. However, in both studies of Coppadoro and colleagues, no associations between CoQ10 and mortality were found [
      • Coppadoro A.
      • Berra L.
      • Kumar A.
      • Pinciroli R.
      • Yamada M.
      • Schmidt U.H.
      • et al.
      Critical illness is associated with decreased plasma levels of coenzyme Q10: a cross-sectional study.
      ,
      • Coppadoro A.
      • Berra L.
      • Kumar A.
      • Yamada M.
      • Pinciroli R.
      • Bittner E.
      • et al.
      Plasma levels of Coenzyme Q10 are reduced in critically ill patients as compared to healthy volunteers and correlate with age.
      ].
      In vitro, CoQ10 decreased oxidative stress and maintained mitochondrial membrane potential [
      • Lowes D.A.
      • Thottakam B.M.V.
      • Webster N.R.
      • Murphy M.P.
      • Galley H.F.
      The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide–peptidoglycan model of sepsis.
      ]. In addition, a recent randomized double-blind pilot trial showed that supplementation with ubiquinol (the reduced form of CoQ10) was able to improve CoQ10 levels in patients with septic shock [
      • Donnino M.W.
      • Mortensen S.J.
      • Andersen L.W.
      • Chase M.
      • Berg K.M.
      • Balkema J.
      • et al.
      Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial.
      ]. However, an RCT in 30 patients with mitochondrial cytopathy receiving 1200 mg/day CoQ10 showed only minor effects of CoQ10 on ergometer cycling exercise aerobic capacity and post-exercise lactate, and no effect on strength or resting lactate [
      • Glover E.I.
      • Martin J.
      • Maher A.
      • Thornhill R.E.
      • Moran G.R.
      • Tarnopolsky M.A.
      A randomized trial of coenzyme Q10 in mitochondrial disorders.
      ]. Further studies are warranted to address whether administration of CoQ10 can result in improved clinical outcomes and mitochondrial function in critically ill patients.

      3.7 Caffeine

      Results of a study in 120 septic rats suggest that caffeine may stimulate oxidative phosphorylation, by restoring complex IV activity. This study also suggested a significantly better survival after caffeine administration [
      • Verma R.
      • Huang Z.
      • Deutschman C.S.
      • Levy R.J.
      Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis.
      ].

      3.8 Melatonin

      A study in mice has demonstrated that melatonin rescued mitochondria from oxidative stress-induced mitochondrial dysfunction and may prevent subsequent cell death of muscle cells [
      • Hibaoui Y.
      • Roulet E.
      • Ruegg U.T.
      Melatonin prevents oxidative stress-mediated mitochondrial permeability transition and death in skeletal muscle cells.
      ]. Several in vitro and in vivo studies demonstrate that melatonin affects mitochondria by increasing the activity of the electron transfer system and ATP production, increasing mitochondrial membrane potential and membrane fluidity and by closing the mitochondrial permeability pore [
      • Leon J.
      • Acuna-Castroviejo D.
      • Escames G.
      • Tan D.-X.
      • Reiter R.J.
      Melatonin mitigates mitochondrial malfunction.
      ,
      • Lowes D.A.
      • Webster N.R.
      • Murphy M.P.
      • Galley H.F.
      Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis.
      ,
      • Acuna-Castroviejo D.
      • Martin M.
      • Macias M.
      • Escames G.
      • Leon J.
      • Khaldy H.
      • et al.
      Melatonin, mitochondria, and cellular bioenergetics.
      ,
      • Garcı́a J.J.
      • Reiter R.J.
      • Guerrero J.M.
      • Escames G.
      • Yu B.P.
      • Oh C.S.
      • et al.
      Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation.
      ,
      • Leon J.
      • Acuña-Castroviejo D.
      • Sainz R.M.
      • Mayo J.C.
      • Tan D.-X.
      • Reiter R.J.
      Melatonin and mitochondrial function.
      ].
      Several small studies measured melatonin levels in critically ill patients. Circadian rhythm of melatonin secretion was disturbed and melatonin secretion low in almost all critically ill patients investigated [
      • Perras B.
      • Kurowski V.
      • Dodt C.
      Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease.
      ,
      • Frisk U.
      • Olsson J.
      • Nylén P.
      • Hahn R.G.
      Low melatonin excretion during mechanical ventilation in the intensive care unit.
      ,
      • Olofsson K.
      • Alling C.
      • Lundberg D.
      • Malmros C.
      Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients.
      ,
      • Mundigler G.
      • Delle-Karth G.
      • Koreny M.
      • Zehetgruber M.
      • Steindl-Munda P.
      • Marktl W.
      • et al.
      Impaired circadian rhythm of melatonin secretion in sedated critically ill patients.
      ]. Low levels of melatonin were associated with more severe illness in septic patients, but not in patients admitted for coronary syndrome, intoxications, gastrointestinal bleeding, pneumonia or stroke [
      • Perras B.
      • Kurowski V.
      • Dodt C.
      Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease.
      ]. Melatonin supplementation was also found to reduce oxidative stress and inflammation in new-borns with sepsis [
      • Gitto E.
      • Pellegrino S.
      • Gitto P.
      • Barberi I.
      • Reiter R.J.
      Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin.
      ]. No published studies were found on the effect of melatonin supplementation on mitochondrial function and clinical outcomes in critically ill patients. However, the study of Mistraletti and co-workers showed a good bioavailability of exogenous melatonin in critically ill patients [
      • Mistraletti G.
      • Sabbatini G.
      • Taverna M.
      • Figini M.A.
      • Umbrello M.
      • Magni P.
      • et al.
      Pharmacokinetics of orally administered melatonin in critically ill patients.
      ].

      3.9 Carnitine

      Carnitine depletion could be expected in patients who undergo prolonged continuous renal replacement therapy, parenteral nutrition for more than 14 days, hypertriglyceridemia or hyperlactatemia [
      • Bonafe L.
      • Berger M.M.
      • Que Y.A.
      • Mechanick J.I.
      Carnitine deficiency in chronic critical illness.
      ]. Primary carnitine deficiency, caused by defects in plasma membrane carnitine transporters in kidney and muscle is uncommon. However, secondary deficiency, caused by disease or as a side-effect of medication, can occur. Indeed, this is observed in conditions with increased catabolism as in critical illness [
      • Evangeliou A.
      • Vlassopoulos D.
      Carnitine metabolism and deficit - when supplementation is necessary?.
      ,
      • Wennberg A.
      • Hyltander A.
      • Sjöberg Å.
      • Arfvidsson B.
      • Sandström R.
      • Wickström I.
      • et al.
      Prevalence of carnitine depletion in critically ill patients with undernutrition.
      ]. Only a few studies assessed the effect of carnitine supplementation on clinical outcome [
      • Hatamkhani S.
      • Karimzadeh I.
      • Elyasi S.
      • Farsaie S.
      • Khalili H.
      Carnitine and sepsis: a review of an old clinical dilemma.
      ,
      • Sarma S.
      • Gheorghiade M.
      Nutritional assessment and support of the patient with acute heart failure.
      ]. Carnitine supplementation appeared to improve outcome in sepsis [
      • Hatamkhani S.
      • Karimzadeh I.
      • Elyasi S.
      • Farsaie S.
      • Khalili H.
      Carnitine and sepsis: a review of an old clinical dilemma.
      ] and acute heart failure [
      • Sarma S.
      • Gheorghiade M.
      Nutritional assessment and support of the patient with acute heart failure.
      ]. Notwithstanding its importance for beta-oxidation and subsequent mitochondrial energy production [
      • Bonafe L.
      • Berger M.M.
      • Que Y.A.
      • Mechanick J.I.
      Carnitine deficiency in chronic critical illness.
      ], effects of carnitine supplementation on mitochondrial function in critical illness have not been studied yet. In general, it is suggested that carnitine supplementation, although not indicated in the healthy population, may be of value in situations characterized by low concentrations of l-carnitine or impaired beta-oxidation, for example, to achieve a higher level of exercise performance [
      • Nicolson G.L.
      Mitochondrial dysfunction and chronic disease: treatment with natural supplements.
      ,
      • Zammit V.A.
      • Ramsay R.R.
      • Bonomini M.
      • Arduini A.
      Carnitine, mitochondrial function and therapy?.
      ,
      • Kraemer W.J.
      • Volek J.S.
      • Dunn-Lewis C.
      L-Carnitine supplementation : influence upon physiological function.
      ].

      3.10 Nitrate

      A study in healthy volunteers showed a better coupling between respiration and oxidative phosphorylation after nitrate treatment (0.1 mmoL/kg/day, divided into three doses). Also, a higher maximal ATP production rate and improved mitochondrial efficiency were found. In addition, results of this study indicate a decreased proton leakage. Finally, mitochondrial density and biogenesis were not affected by nitrate treatment for three days [
      • Bryan N.S.
      • Fernandez B.O.
      • Bauer S.M.
      • Garcia-Saura M.F.
      • Milsom A.B.
      • Rassaf T.
      • et al.
      Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues.
      ]. Nitrate appears to enhance mitochondrial efficiency in healthy persons and probably in populations suffering from muscle weakness and exercise intolerance [
      • Affourtit C.
      • Bailey S.J.
      • Jones A.M.
      • Smallwood M.J.
      • Winyard P.G.
      On the mechanism by which dietary nitrate improves human skeletal muscle function.
      ]. However, in critically ill, in particular, in septic patients, NO production is increased, due to (over) stimulation of the innate immune system [
      • Affourtit C.
      • Bailey S.J.
      • Jones A.M.
      • Smallwood M.J.
      • Winyard P.G.
      On the mechanism by which dietary nitrate improves human skeletal muscle function.
      ]. An even further increase in nitrate/NO levels could be potentially harmful. A study in patients with mitochondrial myopathy did not find an effect of nitrate supplementation for a week on oxygen cost of moderate exercise and mitochondrial function [
      • Nabben M.
      • Schmitz J.P.J.
      • Ciapaite J.
      • le Clercq C.M.P.
      • van Riel N.A.
      • Haak H.R.
      • et al.
      Dietary nitrate does not reduce oxygen cost of exercise or improve muscle mitochondrial function in patients with mitochondrial myopathy.
      ]. Taken together, nitrate supplementation could be beneficial for survivors of critical illness, but should not be administered to patients during the acute phase of critical illness.

      3.11 Α-Lipoic acid

      Evidence of an effect of lipoic acid on mitochondrial function in humans is limited. A case report describing a woman with chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion showed an increased exercise slope of the work-energy cost transfer function reflecting improved mitochondrial activity in muscle, after treatment with 600 mg LA daily for one month [
      • Barbiroli B.
      • Medori R.
      • Tritschler H.-J.
      • Klopstock T.
      • Seibel P.
      • Reichmann H.
      • et al.
      Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo31P-MRS in a patient with mitochondrial cytopathy.
      ]. An RCT assessing the effect of a combination of LA, CoQ10, and creatine in patients with mitochondrial disorders found a reduction in oxidative stress, resting lactate levels and positive changes in body composition [
      • Rodriguez M.C.
      • MacDonald J.R.
      • Mahoney D.J.
      • Parise G.
      • Beal M.F.
      • Tarnopolsky M.A.
      Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.
      ].

      4. Discussion and perspectives

      Our review of the available literature on changes in mitochondrial function during critical illness reveals several knowledge gaps and inconsistencies. The available data suggest that mitochondrial respiration is decreased in muscle cells. Literature also underlines that several nutritional components are pivotal to mitochondrial functioning and that optimizing their availability hold promise to improve the clinical outcome of critical illness. Together, these components form a complex network (Fig. 2). Importantly, mitochondrial bio-energetic functioning will be optimal when substrates and cofactors in this network are available in optimal combinations. Combined deficiencies are probably more common than those of single-nutrient and therefore investigation of combined deficiencies and the role of combined supplementation will be of great interest. Consequently, it is difficult to draw conclusions on the effects of a single nutrient in the oxidative phosphorylation process, as many nutrients cooperate in metabolic pathways. It is likely that supplementation with one nutrient does not improve downstream effects when there is a deficiency of another micronutrient. To make it even more complicated, for almost all described components we lack detailed information on the (normal) status or recommended daily allowance and their association with mitochondrial function and mortality. Furthermore, it is questionable whether plasma levels of nutrients reflect actual availability in mitochondria. Plasma nutrient levels may be low during critical illness due to increased losses through body fluids and increased permeability of endothelium, redistribution, altered protein binding, and inadequate intake. As a consequence, their plasma levels do not likely reflect tissue storages of micronutrients during critical illness. This makes it even harder to interpret the associations found: Is it really a causal inference or does it represent an epiphenomenon only indicating the severity of the disease or even is it reflecting an adaptive response? Moreover, for many nutrients, beneficial effects were only shown in small non-randomized, open-labelled studies and not in large RCTs [
      • Pfeffer G.
      • Horvath R.
      • Klopstock T.
      • Mootha V.K.
      • Bindoff L.A.
      • Yu-wai-man P.
      • et al.
      New treatments for mitochondrial disease—no time to drop our standards.
      ]. Besides, some specific mitochondrial targeting nutrients are developed, such as MitoE and MitoQ, These nutrients are probably more effective in restoring bio-energetic functioning than just restoring plasma levels of the specific micronutrients [
      • Jameson V.J.A.
      • Cochemé H.M.
      • Logan A.
      • Hanton L.R.
      • Smith R.A.J.
      • Murphy M.P.
      Synthesis of triphenylphosphonium vitamin E derivatives as mitochondria-targeted antioxidants.
      ,
      • Leo S.
      • Szabadkai G.
      • Rizzuto R.
      The mitochondrial antioxidants MitoE2 and MitoQ10 increase mitochondrial Ca2+ load upon cell stimulation by inhibiting Ca2+ efflux from the organelle.
      ].
      It should also be kept in mind that bio-energetic failure of the mitochondria is not the only cause of ICU-acquired weakness. Other factors, including but not limited to altered muscle membrane excitability due to sodium and calcium channel abnormalities and excitation-contraction uncoupling due to altered calcium homeostasis and myofibrillar calcium insensitivity are important processes in muscle weakness [
      • Batt J.
      • Mathur S.
      • Katzberg H.D.
      Mechanism of ICU-acquired weakness: muscle contractility in critical illness.
      ].

      4.1 Recommended research

      Although this field holds several promises, much remains to be investigated on the underlying mechanisms and potential of targeted nutritional intervention in preventing or combating negative health outcomes of critical illness. Important gaps exist 1) in relation to our general knowledge on mitochondrial dysfunction during disease, both on the short- and the long-term, and 2) the effects of nutritional components, in particular in combination in human patients during different stages of the disease process. Regarding the first point, well-controlled cohort studies seem warranted in which monitoring of health parameters is combined with physiological and biochemical measurements. Ideally, these studies should include metabolic and functional parameters of muscle tissue. To measure mitochondrial function, in vitro or ex vivo strategies have been used, which provides information on maximal (OXPHOS) enzyme activities using saturated metabolites. Although this is very informative it does not take the nutritional status of the patients into account. Therefore, this field of research would greatly benefit from in vivo (non-invasive) real-time assessments of mitochondrial function. Approaches that could be used are 1) indirect calorimetry to measure in vivo substrate oxidation [
      • Oshima T.
      • Berger M.M.
      • De Waele E.
      • Guttormsen A.B.
      • Heidegger C.-P.
      • Hiesmayr M.
      • et al.
      Indirect calorimetry in nutritional therapy. A position paper by the ICALIC study group.
      ], 2) Phosphorus NMR spectroscopy to measure phosphocreatine, ATP, inorganic phosphate, and 3) near-infrared spectroscopy (NIRS) to measure in vivo muscle oxygen consumption [
      • Campbell M.D.
      • Marcinek D.J.
      Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods.
      ]. This altogether provides a wealth of information on in vivo mitochondrial functioning. Next to this, transcriptomic and proteomic (muscle, immune cells) and metabolomic (urine) analyses will help to find biomarkers and to reveal underlying mechanisms. Regarding the second point, there is currently insufficient knowledge on the role of combinations of nutrients to stimulate mitochondrial function in critically ill patients. Even information on `normal' plasma and tissue levels of micronutrients during critical illness is often lacking. Despite the limitation that plasma levels do not necessarily reflect what happens in tissues, such information remains useful, in particular when performed as part of cohort studies following patients during and after their discharge from the ICU.
      Nutritional intervention and (or) supplementation studies should address the issue of combined effects, supplementation with single nutrients is discouraged. When performing such studies, bio-availability and other kinetic factors, as well as the real-time assessment of mitochondrial function should be considered. Translational studies may be warranted to assess the effects of supplementation with one or more substance(s) on mitochondrial function.

      5. Conclusion

      Taken together, the evidence that impairment of mitochondrial bio-energetic function in muscle plays a crucial role in determining recovery from critical illness is convincing. As the underlying mechanisms involve different pathways and processes, ‘multiple-target’ strategies are best suited to correct the imbalances. Promising candidate molecules include several nutritional components.

      Authors contribution

      E. Wesselink and A.R.H. van Zanten contributed to the conception and design of the manuscript. E Wesselink contributed to the acquisition and interpretation of the data. E. Wesselink drafted the manuscript. W.A.C Koekkoek, S. Grefte, R.F. Witkamp and A.R.H van Zanten critically revised the manuscript. All authors approved the final version.

      Conflicts of interest

      Dr. van Zanten reported that he has received honoraria for advisory board meetings, lectures, and travel expenses from Abbott, Baxter, BBraun, Danone-Nutricia, Fresenius Kabi, Lyric, and Nestlé-Novartis. Inclusion fees for patients in the MetaPlus trial from Nutricia were paid to the local ICU research foundation.
      The remaining authors have disclosed that they do not have any conflicts of interest.

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