Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called “cytopathic hypoxia,” perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system (“immunoparalysis”) translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.
Sepsis is a potentially lethal condition defined by life-threatening organ dysfunction caused by a dysregulated host response to infection [
The combination of hypotension, vasopressor use, and lactate level greater than 2 mmol/L, defining septic shock under Sepsis-3 terminology, is associated with hospital mortality rates consistently higher than 40%. These prohibitive mortality rates remain roughly unchanged despite extensive fundamental research and on-going medical progress. Understanding the pathophysiology of septic shock-induced multiorgan failure (MOF) thus remains a prerequisite to improve its outcome.
However, fundamental events driving the pathological processes of septic shock-induced MOF at the cellular and subcellular levels remain controversial [
Sepsis-induced failure of
However, comprehensively addressing septic shock-induced skeletal muscle and PBMC dysfunctions remains an unmet need. Therefore, our goals are to focus on these specific points and to stress how and why cellular and subcellular failure impair ICU outcome in patients who overcome the acute phase of septic shock. The role of persistent mitochondrial dysfunction in skeletal muscles and PBMC is specifically scrutinized. To conclude, we emphasize how mitochondrial-targeted therapies could improve long-term recovery after septic shock.
Mitochondria are ubiquitous powerhouses of eukaryotic cells and they provide organisms with adenosine triphosphate (ATP) by using a group of enzymes, gathered in the mitochondrial electron transport chain (ETC), which transform transmembrane electron potential (
A small part of oxygen, not used for oxidative phosphorylation, leads to the mitochondrial production of ROS at complexes I and III through uncoupling [
Mitochondrial hormesis (otherwise named mitochondrial biogenesis) is a cellular programed process that adjusts energy production by synthesis of new organelles and regulation of interorganelle interactions. The mitochondrial response to stressors (including sepsis) is sharply orchestrated by peroxisome proliferator-activated receptor-
Other functions of mitochondria include synthesis of steroid hormones [
Mitochondrial dysfunction encompasses multiple aspects of disturbed cellular homeostasis, including decreased ATP production, increased generation of ROS, calcium dysregulation, and mtDNA damage [
In vitro, sepsis-associated systemic inflammation produces ROS and reactive nitrogen species (RNS) primarily within the cytosolic NADPH oxidase [
Due to its vicinity of the ETC and its lack of protection by histones, mitochondrial DNA is very susceptible to oxidative and nitrosative stress [
In vitro [
In humans, it is hypothesized that dysfunctional mitochondrial respiratory chain results in reduced ATP turnover and metabolic shutdown. When metabolic shutdown is sufficiently intense to prevent adequate production of ATP, cells can no longer maintain energy availability for essential cellular functions and go into either necrotic or apoptotic cell death pathways [
Succession of events leading to sepsis-induced mitochondrial dysfunction. (1) Increased activity of inducible NO-synthase. (2) Increased mitochondrial superoxide anion generation. (3) Production of peroxynitrite. (4) Nitrosylation of respiratory chain complexes. (5) Decreased membrane potential. (6) Opening of mitochondrial transition pore. Greek numbers refer to mitochondrial complexes. iNOS: inducible nitric oxide synthase; NO: nitric oxide;
However, the initial multiorgan metabolic shutdown may be revocable, since most organs recover when the septic patient overcomes his infectious episode [
If the organism (either animal or human) survives, as septic shock recovers, prolonged exposure to lower levels of NO activates mitochondrial biogenesis that promotes mitochondrial proliferation and a progressive increase in cell metabolism [
Nucleus-mitochondria crosstalk for apoptosis and mitochondrial hormesis induction: key role of PGC-1
The switch from mitochondrial metabolic shutdown to mitochondrial biogenesis is finely regulated and orchestrated by many factors that ultimately depend on sepsis severity and resilience of the organism [
ICU-acquired weakness is now a recognized clinical consequence of skeletal muscle mitochondrial dysfunction [
As it extends ventilator-dependent duration, ICU-acquired diaphragm weakness may increase persistent functional limitation, the incidence of ventilator-associated pneumonia, and healthcare-associated morbidity.
In a murine model of septic shock, Zolfaghari et al. demonstrated that maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice, together with lower mitochondrial
Even if clinical evidence of sepsis-induced direct diaphragm mitochondrial dysfunction is still lacking in man, mechanical ventilation was shown to induce profound defects in diaphragm mitochondrial biogenesis and cytochrome c oxidase content in ventilated brain-dead organ donors [
Concerning limb muscles, deficits in both strength and size may exceed those seen in the diaphragm. For instance, Mofarrahi et al. reported reduced resistance to increased Ca2+ load and deeper biogenesis reduction in locomotor muscles (
Experimental findings suggest that prolonged and unopposed inflammatory processes during sepsis amplify TNF
However, based on recent data from our team and others, implication of a circulating plasmatic factor remains unclear to account for muscular mitochondrial ETC decreasing activity in both experimental models and septic shock patients. For instance, in a short-term CLP-induced murine septic shock model, ex vivo mitochondrial assessments showed neither reduced enzymatic activities, altered mitochondrial respiration, nor reduced tolerance to calcium loading [
Pioneering studies from Mervyn Singer’s laboratory established that mitochondrial ETC was severely impaired in skeletal muscle biopsies from septic shock patients [
Using microarray analysis the Singer’s team consequently demonstrated that septic shock survivors were able to activate mitochondrial hormesis pathways (PGC-1
As mitochondria used to be ancient endosymbiotes, defence mechanisms from the host immune response directed towards the non-self also recognize molecular patterns shared by mitochondria (containing many DAMPs) and pathogen agents (PAMPs) [
Initially, exhaustion of the immune system leads to immunoparalysis. Potential mechanisms of immune suppression in patients with septic shock include shift from proinflammatory to anti-inflammatory phenotype, lymphocyte mitochondrial energy and apoptosis-induced depletion of CD4 positive cells and dendritic cells [
Septic shock is classically associated with lymphopenia [
In a murine sepsis model of caecal ligation and puncture, Chang et al. have shown that downregulation of genes involved in mitochondrial-mediated apoptosis (
In humans, involvement of mitochondrial-mediated apoptosis in sepsis has been evidenced by a caspase-9-mediated profound progressive loss of B and CD4+ T cells [
Lymphocyte mitochondrial dysfunction has been shown in sepsis and was ascertained by an early decrease in mitochondrial respiratory capacity. Garrabou et al. observed a 16% decrease in spontaneous cell oxygen consumption in PBMCs from severe sepsis patients. Concurrent apoptosis process was shown in septic patients by an elevated caspase-3 activity and by a much higher percentage of cells with depolarized mitochondria. No change in cell mitochondrial content was observed at that stage [
Mechanisms leading to mitochondrial dysfunction in circulating lymphocytes remain unclear. In the vein of muscular mitochondrial dysfunction, the influence of septic plasma has been suggested. Indeed, Belikova et al. observed a lower response to ADP stimulation and an increased fraction of decoupling oxygen consumption in septic PBMC and in healthy PBMC after incubation in septic plasma, whereas septic PBMC incubated in healthy plasma partially recovered normal respiratory capacities [
Functional alterations in PBMCs may also account for septic shock-induced immunosuppression. For instance, Weiss et al. demonstrated that mitochondrial SRC was reduced and uncoupled respiration was increased in septic shock children PBMCs compared to controls, suggesting that mitochondria within immune cells could not keep pace with an increase in energy demand [
In septic shock survivors, mitochondrial recovery, and biogenesis have been suggested [
Time course of mitochondrial impairment and mitochondrial biogenesis following sepsis in peripheral blood mononuclear cells (PBMCs). TNF
Moreover, increase of mitochondrial biogenesis was associated with lymphocytes functional improvements, such as CD8+ T cell memory development in mice [
These results suggest that initial mitochondrial dysfunction in sepsis would induce both quantitative and qualitative impairments of immune cells and that mitochondrial biogenesis may subsequently compensate for these deficiencies by an increased mitochondrial mass and a higher resilience to stressors.
Even if a causative link still has to be demonstrated between sepsis-induced muscle weakness/immunoparalysis on the one hand and increased incidence of ventilator-acquired pneumonia on the other hand, many indices converge to a common pathophysiologic pathway. Indeed, sepsis-induced ICU-acquired muscle weakness triggers diaphragmatic dysfunction, weaning failure, and prolonged mechanical ventilation, which is associated with increased mortality when weaning is prolonged above 7 days [
Actually, swallowing disorders and reduced cough strength decrease airway clearance and increase the pathogen load (bacterial, viral, and fungal) to the lungs. If immune response effectors are also worn-out, pathogens can develop unrestrainedly. From the immunological point of view, severe persistent sepsis-induced lymphopenia was associated with increased development of secondary infections and death [
As mitochondrial dysfunction in skeletal muscle and PBMC potentially contributes to protracted weaning from mechanical ventilation and persistent infectious foci in patients recovering from septic shock, therapies promoting mitochondrial healing may favour recovery of both muscular functions and immunologic potency. Efforts should be made to focus on the good treatment in the right place and at the appropriate time.
Even if restricted oxygen uptake and global tissue hypoxia may trigger inflammatory cascade at the onset of sepsis [
As complex I is predominantly damaged during sepsis [
The process of
Resveratrol, a natural phenol within red grapes [
However, some antioxidants may fail to induce mitohormesis, due to inadequate mitochondrial upload, and mitochondrial-targeted therapies hold promises. In mechanically ventilated mice, Picard et al. demonstrated that transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3, downregulated in mechanically ventilated human diaphragms) was protective against ventilation-induced diaphragmatic dysfunction [
Among research possibilities to confirm the key role of initial mitochondrial dysfunction in sepsis, antioxidants could therefore be used to improve mitochondrial work at an early stage of sepsis, in order to diminish mitochondrial-mediated ROS production and apoptosis. Besides, regulation of genes involved in lymphocytes mitochondrial-mediated apoptosis (e.g., Bcl-2) and TLR2-mitochondria axis deserve to be more studied [
The “tissue hypoxia” paradigm in sepsis has recently been challenged and should prompt research in the field of cytopathic hypoxia. In septic shock patients, a circulating factor (which could be nitric oxide, superoxide anion, peroxynitrite, or mtDNA) induces mitochondrial ETC dysfunction and increases apoptosis in both myocytes and PBMCs. These processes profoundly impair organ recovery and patient rehabilitation. Therapeutic induction of mitochondrial hormesis (increased mitochondrial mass and a higher resilience to stressors) may be a way to overcome the septic episode and might stand for a promising research to promote organ recovery in critical illness.
Protein kinase B
Adenosine triphosphate
Compensatory anti-inflammatory response syndrome
Mitochondrial transmembrane electron potential
Electron transport chain
Early goal-directed therapy
Oxidized flavin-adenine dinucleotide
Reduced flavin-adenine dinucleotide
Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone
Glycogen synthase kinase 3
Intensive care unit
Inducible nitric oxide synthase
Multiorgan failure
Mitochondrial permeability transition pore
Mitochondrial desoxyribonucleic acid
Oxidized nicotinamide adenine dinucleotide
Reduced nicotinamide adenine dinucleotide
Nitric oxide
NOD-like receptor family, pyrin domain containing 3
Nuclear respiratory factors
Peripheral blood mononuclear cells
Peroxisome proliferator-activated receptor-
Reactive nitrogen species
Reactive oxygen species
Sirtuin
Silent mating type information regulator 2 homolog 1
Manganese superoxide dismutase
Sepsis-Related Organ Failure Assessment
Spare respiratory capacity
Mitochondrial transcription factor A
Toll-like receptor.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Quentin Maestraggi and Benjamin Lebas were involved in the writing of the first section of the review. Raphaël Clere-Jehl, Thiên-Nga Chamaraux-Tran, and Pierre-Olivier Ludes were involved in the writing of the second section of the review. Francis Schneider, Pierre Diemunsch, and Bernard Geny were involved in drafting the manuscript and revising it critically for important intellectual content. Julien Pottecher conceived the review and drafted the manuscript. All authors read and approved the final manuscript.