Secondary Logo

Journal Logo

Review Article

Mitochondrial Function in Sepsis

Arulkumaran, Nishkantha; Deutschman, Clifford S.; Pinsky, Michael R.; Zuckerbraun, Brian; Schumacker, Paul T.; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A. on behalf of the ADQI XIV Workgroup

Author Information
doi: 10.1097/SHK.0000000000000463
  • Free



The authors were tasked with developing five specific questions regarding mitochondrial function in sepsis within the context of the Acute Dialysis Quality Initiative 14 (ADQI XIV) meeting held in Bogotá, Colombia, in late 2014. The authors presented these questions to the rest of the panel of participants and from group discussions focused these questions to address specific aspects of mitochondrial function. Then off-line reviewed the literature and complied the answers to these questions which were vetted by all authors before publication. What follows is the synthesis of this effort arranged under the heading of five key questions.


Complete methods are available in the companion article to this series. (ref) Briefly, we assembled a group of international experts with distinct clinical and scientific backgrounds; this group included physicians, specialists in critical care, anesthesiology, nephrology, surgery and emergency medicine, and basic scientists with expertise in biology and physiology, who were recruited based on their expertise in sepsis and organ dysfunction. The group consisted of 23 international experts from 5 continents. A set of questions were generated through mutual agreement, and we sought evidence to answer each question by searching the Cochrane Controlled Trials Register, the Cochrane Library, MEDLINE, and EMBASE from 1966 to present. Search terms for question regarding epithelial dysfunction are provided in Appendix B. Finally, we reviewed the evidence with the group and used the Delphi method to achieve consensus.


Based on literature review and consensus among the workgroup members, the following key questions were considered:

  1. Are mitochondria the initiators, amplifiers, victims, or innocent bystanders in the organ dysfunction in sepsis?
  2. To the extent that mitochondria are disrupted in sepsis, is the molecular mechanism related to bioenergetic function, oxygen-dependent oxidative phosphorylation, cell death regulatory functions, biosynthetic, regulatory, or stress-related signaling (e.g., reactive oxygen species [ROS]) functions? What is the relationship between endothelial altered function and organ function?
  3. To what extent does a disruption in mitochondrial dynamics and homeostasis contribute to cellular and organ system dysfunction in sepsis?
  4. Is the trade-off between “cell-adaptive” and “organ-maladaptive” responses a driver of organ dysfunction and long-term recovery in sepsis? Do organ-specific differences in this dichotomy determine outcome?
  5. What are the mitochondria-based therapeutic targets and opportunities for intervention?

Question 1. Are mitochondria the initiators, amplifiers, victims, or innocent bystanders in the organ dysfunction in sepsis?

Although a number of studies have assessed mitochondrial morphology and function in experimental models of sepsis and in critically ill patients, the relationship between mitochondrial function and organ system dysfunction is not fully elucidated. Figure 1 shows the known roles mitochondria play during sepsis. Furthermore, Table 1 groups the cited studies into groups based on their reporting on these various aspects of mitochondrial health and function. Stresses associated with the systemic response to sepsis, including oxidative and nitrosative stress, can contribute to mitochondrial dysfunction (1–15). Conversely, mitochondria can function as a source of oxidant stress. Studies have described evidence of mitochondrial damage in critically ill patients and in experimental models of sepsis, but it is not clear whether this association represents organelle damage as a consequence of inflammation arising from the response to infection, or whether the changes in mitochondria are etiologic in the development of cellular and organ dysfunction. Evidence suggests that signals from healthy mitochondria can activate stress responses in cells, they can activate transcription factors, including hypoxia-inducible factor-1α (HIF-1α), NFκB, and p53, and they can initiate a suppression of metabolic activity mediated by activation of adenosine monophosphate (AMP)-dependent protein kinase (AMPK). Pathology samples from patients with critical illness frequently reveal normal cellular morphology despite organ system dysfunction. This raises the question of whether signals from mitochondria could be responsible for suppressing cellular function, possibly as an adaptive mechanism to preserve cell survival. So, it is possible that in some cases mitochondria are damaged during the response to sepsis, that in other cases the generation of oxidants by mitochondria could induce or amplify tissue dysfunction, and yet in other cases the changes in mitochondria may represent a downstream marker of tissue damage. Further studies are needed to determine the significance of each of these roles in the septic patient.

Fig. 1
Fig. 1:
Metabolism and cell signaling.
Table 1
Table 1:
Mitochondrial monitoring and functions

Question 2. To the extent that mitochondria are disrupted in sepsis, is the molecular mechanism related to bioenergetic function, oxygen-dependent oxidative phosphorylation, cell death regulatory functions, biosynthetic, regulatory, or stress-related signaling (e.g., reactive oxygen species [ROS]) functions?

Bioenergetic function and oxygen-dependent oxidative phosphorylation

A functional alteration in O2 consumption (VO2)-related metabolism may occur in sepsis (i.e., dysoxia). In resuscitated septic patients who have an increase in global O2 delivery and adequate tissue perfusion, “non-vital organ” (e.g., skeletal muscle) O2 tension remains elevated, suggesting a decrease in local VO2 even though global VO2 may increase (16, 17). The mechanism underlying this reduction in regional O2 utilization may be a consequence of changes in the mitochondrial respiratory chain complexes.

Respiratory protein subunits and transcripts for complexes I and IV were downregulated in critically ill patients, with a more prolonged recovery course and greater reduction in adenosine triphosphate (ATP) levels in eventual nonsurvivors (18, 19). Acute endotoxemia decreased cardiac muscle mitochondrial O2 consumption and complex I activity, a change that was associated with decreased ATP synthesis and ATP content (20), whereas cecal ligation and puncture (CLP) models show decreased complex IV activity, a change associated with decreased contractility. During sepsis, there is a significant increase in nitric oxide (NO), mediated in part by increased inducible nitric oxide synthase (iNOS) activity. The reaction of NO with superoxide generates peroxynitrite, a “reactive nitrogen species” (RNS) (21). Mitochondrial complexes I and IV are susceptible to persistent inhibition from nitrosylation and perhaps nitration ex vivo(22), and inhibition of NO ameliorates the impaired mitochondrial respiration in endothelial cells exposed to serum from septic patients (23).

In addition to mitochondrial complex expression and activity, cytochrome c oxidase (CCO) was inhibited in a mouse model of sepsis induced by CLP. CCO inhibition was initially competitive, but after 48 h became noncompetitive (24). Exogenous cytochrome c administered at 24 h after induction of sepsis restored cardiac mitochondria activity, increased cytochrome oxidase kinetic activity, and improved cardiac function (25). Exogenous cytochrome c 24 h post-CLP repleted mitochondrial substrate levels for up to 72 h, restored myocardial cytochrome oxidase activity, and improved both contractility and survival (26). Caffeine administration 24 or 48 h following CLP also improved CCO activity, restored cardiac contractility, and improved survival (27)

There are discrepancies in the literature with regard to changes in complex activity in different muscle groups and organs in sepsis (26, 28) and endotoxemia (29–31). This discrepancy has been attributed to differences in the organs studied (31), the time point of measurement, species involved, and severity of illness. Importantly, changes in endotoxemia differ from those observed following CLP. Indeed, much of the controversy surrounding the effects of sepsis on mitochondria may reflect the inherent differences between LPS administration, an acute inflammatory state, and more clinically relevant models, such as CLP (32–34).

Biosynthetic functions

Hypoxemia, which alters mitochondrial function, may be associated with sepsis. The responses to hypoxia include the upregulation of hypoxia-inducible factors, vascular endothelium growth factor (VEGF), and glycolytic enzymes to maintain ATP production.

During normoxic conditions, constitutively expressed prolyl hydrolyxase hydroxylates HIF-1α, which leads to proteosomal degradation of HIF-1α (35). Hypoxia-induced mitochondrial ROS (mtROS) are responsible for HIF-1α stabilization. Cells with functional electron transport chain (ETC) deficiencies or cells treated with ETC inhibitors cannot produce ROS and failed to stabilize HIF-1α (36, 37). Cells lacking complex III subunit cytochrome b were able to produce ROS, but could not carry out oxidative phosphorylation, implicating the former in HIF-1α stabilization (38). Hypoxia and the mtROS increases also increased VEGF transcription (39) and the contractile response of pulmonary arterial smooth muscle cells (40).

Immune functions

mtROS are potent initiators of the innate immune system. Inhibition of ETC complex I or III provoked a dose-dependent increase in mtROS production and NLRP3 activation in a human THP1 macrophage cell line (41). NO downregulated mtROS-induced NLRP3 inflammasome activity and was protective in endotoxemia (42).

Macrophage clearance of bacteria involves phagocysis and ROS-mediated degradation of the pathogen. ROS in phagosomes, in turn, are produced by NADPH oxidase (NOX) and by an increase in uncoupling protein 2 (UCP-2) expression (43). mtROS also modulate Toll-like receptor (TLR) pathways. Depletion of mtROS by catalase overexpression impaired clearance of intracellular organisms (Salmonella typimurium) (44). mtROS also function downstream in TLR-activated signaling pathways such as tumor necrosis factor (TNF)-mediated activation of NF-κB (45).

Oxidative stress

Superoxide is the primary oxidant produced by mitochondria respiratory complexes I, II, and III. In health, levels of superoxide are contained by manganese superoxide dismutase (MnSOD), which is confined to mitochondria. NO reacts with superoxide to generate the peroxynitrite and other RNS, (21) which are potent oxidizing agents and have been implicated in protein nitration, DNA damage, and mitochondrial dysfunction in isolated mitochondria and in cells treated with serum from septic patients (23, 46). Diaphragmatic and cardiac mitochondrial O2 and H2O2 production were increased up to 3-fold during endotoxemia, and MnSOD activity showed a 2-fold increase in LPS-treated animals (47).

Mitochondria exposed to non-mtROS may become a source of ROS themselves. Renal tubular cells increase their expression of iNOS and NADPH oxidase 4 (NOX-4) in response to LPS. This process can culminate in the cytosolic overexpression of NO and superoxide anion, the primary RNS and ROS, respectively (48), a positive feedback loop that may result in dysregulation of mitochondrial function.

Treatment with antioxidants ameliorates organ injury in experimental models of sepsis. Therapeutic agents tested include N-acetyl cysteine (49) in hepatic oxidative stress and MITO-Tempo in renal injury (50). Limiting the production of peroxinitrite abundance (with tetrakis-[1-methyl-4-pyridyl] porphyrin pentachloride, MnTMPyP, a peroxinitrite which prevents decomposition catalyst or with NO with aminoguanidine [AG], a NOS-2 inhibitor) (AG) prevented renal injury (51).

Cell death

ATP depletion, loss of mitochondrial membrane potential, release of cytochrome C, and oxidative stress can lead to apoptosis by altering the mitochondrial permeability transition (MPT) (52). Upon depletion of ATP, Ca+2 homeostasis cannot be maintained, and the MPT is induced, followed by cell death (53). Drugs such as cyclosporine A or carnitine inhibit MPT opening (54). Lymphocyte apoptosis is associated with immuneparesis and increased mortality among septic patients. The mechanism behind increased lymphocyte apoptosis is multifactorial, though cell death via mitochondrial-mediated apoptosis has been implicated. Apoptotic lymphocytes derived from septic patients contained active caspase 8 and caspase 9, consistent with death occurring by both mitochondrial- and receptor-mediated pathways (55).

Temporal changes in mitochondrial function

The relationship between sepsis-induced changes in mitochondrial function and organ dysfunction/recovery is time-dependent and has important therapeutic implications. Alterations to respiratory protein subunits and transcripts occur within the first 24 h of ICU admission and correlate with eventual outcome (19). Skeletal muscle antioxidant reserves are reduced within 48 h of ICU admission, and are associated with mortality (18). It remains unclear when these changes begin to normalize. The production of mtROS probably occurs early in sepsis, as it has a key role in innate immunity. It is unclear when generation of mtROS ceases to be adaptive and becomes damaging. Lymphocyte apoptosis, although multifactorial, is a late phenomenon (56).

Monitoring mitochondrial health

At present, monitoring of mitochondrial health is limited to experimental work. Promising real-time in vivo techniques include NADH fluorometry, magnetic resonance spectroscopy, and near-infrared spectroscopy to measure COX redox state (57). Mitochondrial O2 tension can be estimated by measurement of the phosphorescence decay time of sensors containing protoporphyrin IX (58). These techniques have shown promise in animal models of different shock states and warrant further investigations in sepsis.

Mitochondria in circulating cells may provide insight into sepsis-associated temporal changes and how these changes relate to recovery. Respiratory chain biochemistry in platelets is variably inhibited, with no convincing association with either severity of illness or mortality (31). Reduced complex activity in platelets is not a consistent finding (59), and may be time-dependent. Decreases in mitochondrial bioenergetic reserve and increased uncoupling have been observed in peripheral blood mononuclear cells obtained from septic children. A higher mononuclear mitochondrial membrane potential on days 1 to 2 was associated with reduced organ injury by day 7 (60). The application of mitochondrial bioenergetic assessment in circulating cells requires further validation, and holds promise for monitoring illness progression and therapeutic interventions.

Question 3. To what extent does a disruption in mitochondrial dynamics and homeostasis contribute to cellular and organ system dysfunction in sepsis?

Multiple stressors have been shown to influence all known mitochondrial functions, including oxidative phosphorylation, as well as biosynthetic, regulatory, and signaling functions. To carry out this complex array of activities, it is critical to maintain a population of viable mitochondria, typically defined as maintenance of normal global mitochondrial membrane potential (61).

Several responses allow the mitochondrial network to adapt to stress and a loss of membrane potential. These include mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis (62–65).

Mitochondrial fission and fusion responses are dynamic morphological changes that occur in the mitochondrial network (66). Fission is recognized as a coordinated process whereby the mitochondrial network sequesters damaged elements of the mitochondria to a focal region, and this area is then “pinched off” to maintain the overall health of the network. Mitochondrial fusion can promote complementation where a mildly damaged mitochondrion is assimilated into the healthier network, resulting in an overall maintenance of membrane potential. These processes have been studied minimally in the setting of sepsis. In a preclinical animal model of sepsis (CLP), there was an abnormal balance of fission and fusion responses thought to contribute to cellular injury and apoptosis. The in vivo pretreatment with mdivi-1 (Drp1 inhibitor) significantly attenuated mitochondrial dysfunction and apoptosis in CLP (67).

Autophagy is a well-conserved, intracellular, catabolic process where proteins and organelles are isolated within a double membrane vesicle (autophagosome), targeted to the lysosome for degradation (68–70). Specifically, mitochondrial autophagy (or mitophagy) can consume damaged and dysfunctional mitochondria. Individual depolarized mitochondria, thought to be separated from the network through fission, are targeted for autophagosome formation and lysosomal degradation (71). This process serves to eliminate the depolarized and damaged mitochondria that may otherwise produce oxidant stress within the cell, as well as release mitochondrial contents into the cytosol or extracellular space, which can promote inflammatory and immune responses.

A number of clinical studies have illustrated increased autophagocytic signaling in multiple organs and tissues in sepsis (72). In addition, autophagy has been demonstrated in numerous animal models of sepsis or endotoxemia. Inhibition of autophagy in a CLP model resulted in increased apoptosis and organ injury (73). Moreover, in a burn wound model in rabbits, insufficient autophagy was more pronounced in nonsurviving than in surviving animals, a finding that correlated with impaired mitochondrial function and more severe organ dysfunction (74). In contrast, key substrates and controllers associated with mitochondrial fusion/fission or biogenesis were not significantly different regarding survival status. Multiple preclinical studies have used nonspecific pharmacologic approaches that enhance autophagy and have demonstrated amelioration of organ injury (75–77).

Mitophagy/autophagy blockade results in the accumulation of depolarized mitochondria, and increased ROS generation with an associated activation of the NLRP3 inflammasome (78). Similarly, in vitro studies of macrophages stimulated with LPS and ATP led to ultrastructural damage of the mitochondria and increased cytosolic levels of mitochondrial DNA (mtDNA). Inhibition of autophagic signaling was manipulated and impaired; this process was exacerbated with augmented release of IL-1β and IL-18 (79).

Mitochondrial biogenesis refers to the process of the generation of new mitochondria, which is a coordinated effort of transcription and translation, involving both mitochondrial and nuclear genomes. The generation of new mitochondria is potentially critical to meet cellular metabolic energy demands and to fulfill other roles, including calcium homeostasis, maintenance of cellular redox state, and cell signaling. In muscle biopsies of septic patients, the transcriptional coactivator of mitochondrial biogenesis, PGC-1α, was significantly elevated in survivors. Survivors also had higher muscle ATP levels and a decreased phosphocreatine/ATP ratio (80). In patients with acute illness, skeletal muscle biopsies harvested from intensive care unit patients with organ dysfunction demonstrated a 2-fold decrease in mitochondrial content (81). In preclinical models of sepsis, the onset of mitochondrial biogenesis has been shown to correspond to the restoration of normal mitochondrial oxidative respiration (82). The course of sepsis and recovery is characterized by an increment in markers of mitochondrial biogenesis and mitochondrial number and density (83).

Biogenesis and autophagy have been linked in several preclinical models of sepsis. One study suggested that mitochondrial biogenesis was dependent on an autophagy and mtDNA/Toll-like receptor 9 (TLR9) signaling (83).

Another study using an endotoxemia model demonstrated a simultaneous increase in mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This was associated with lower levels of lung and mitochondrial injury, as well as reactive oxygen species and improved survival (84).

In addition, it is important to consider the temporal aspects of mitochondrial functions and dynamics as they relate to the stage of the disease process, specifically infection and sepsis. The biology inciting sepsis involves a complex interplay of microorganisms and host/host responses. It has been hypothesized that a decrease in mitochondrial function, which may lead to or coincide with a loss of critical cell-specific functions, may be an adaptive response that prevents cell death to allow for eventual recovery (85–87). Downregulation of certain mitochondrial functions, including oxidative phosphorylation, may be aimed at limiting the production of ROS which would otherwise damage cells further. It has been hypothesized that these responses are akin to cellular estivation (i.e., hibernation), allowing for a “slowing down” of energy utilizing processes. However, temporally there must also be restitution processes (including biogenesis) to allow for eventual recovery.

The complex interplay of these mitochondrial dynamics and homeostasis responses is critical to cell biology in response to stress. Further studies in preclinical models and in patients highlighting the relationship and temporal aspects of these processes are necessary. This potentially will guide the development of targeted therapies to harness adaptive and minimize maladaptive responses.

Question 4. Diverse cells respond to stresses (e.g., hypoxia, cytokines, mechanical deformation) by activating mitochondria-dependent signals that trigger cellular protective responses. Ischemic preconditioning is one such example. However, responses that are adaptive for survival of the individual cell may be detrimental for tissue/organ function. Is the trade-off between “cell-adaptive” and “organ-maladaptive” responses a driver of organ dysfunction and long-term recovery in sepsis? Do organ-specific differences in this dichotomy determine outcome?

The triggering of “danger” signals leads to the activation of a number of protective responses (88). “Danger,” in turn, may arise from a number of different stimuli. When confronted with even relatively mild hypoxia, protective mechanisms decrease potential damage should the reduction in the oxygen supply become critical (89). Inflammation, sensed via the binding of danger-associated molecular patterns or pathogen-associated molecular patterns to TLR receptors, is known to initiate protective mechanisms via the MyD88/TRADD/NF-κB and JAK1/STAT3 pathways (90). Responses linked to mechanical deformation may be the result of nuclear compression (91). It appears that the cellular response to these “danger” signals is modulated by mitochondria.

Responses to hypoxia lie, in part, in the terminal cytochrome oxidase, complex IV, which binds oxygen, and thus can respond to critical hypoxia (89). Interestingly, potentially protective responses are activated at O2 concentrations that do not compromise the synthesis of ATP: complex IV continues to consume oxygen at a constant rate even as the O2 levels decrease. Therefore, diminished ATP levels cannot be responsible for triggering protective responses until the oxygen supply becomes critically low. Electron transport, however, is in flux even when oxygen consumption and ATP generation are maintained. Even mild hypoxia can limit the reoxidation of cytochrome c. As the cytochrome c pool becomes progressively more reduced, the capacity to absorb electrons is limited and the transfer of electrons to complex IV becomes impaired. Electron transfer from complex III is limited with a resultant increase in the generation of ROS: limiting the activity of complex IV increases electron density at complex III and results in enhanced generation of O2(89). The generation of ROS has also been implicated in cytokine- and deformation-mediated signaling. Proinflammatory cytokines such as TNF, IL-1 (via TLR-MyD88-mediated NF-κB activation), and IL-6 (via JAK-1/STAT3 activation) accelerate ROS production and augment the release of Ca+2 and proapoptotic proteins (90, 92, 93). These processes damage mitochondria, accelerating mitophagy and activating NRF-2, HO-1, AMPK, and SIRT-1. In addition, these stimuli activate nuclear paradigms that promote biogenesis (90). A rising ratio of AMP to ATP indicates energy supply limitations, with AMPK-mediated blockade of ATP-consuming processes, especially mitogenic pathways controlled by mTOR (94). Perturbations of cell architecture, such as those accompanying mechanical deformation, affect membrane potential by altering mitochondrial volume (91), an effect that likely results in ROS liberation (95, 96).

In addition to direct damage to membranes via lipid peroxidation, enhanced ROS production activates HIF-1α (97, 98). HIF-1α is a heterodimeric protein transcription factor that, under unstressed conditions, is inactive. Cellular abundance of the active heterodimer is low because continuous hydroxylation of proline residues targets the HIF-1α subunit for proteosomal degradation (97, 99). ROS prevent degradation, stabilizing the heterodimer and facilitating HIF-1α-mediated transcription (98).

One consequence of the activation of a “danger response” pathway in cells is a reduction in cellular activity beyond the level of maintenance of basic cellular integrity. Under this paradigm, cells suppress some energy-dependent activities in favor of those that are essential for cell survival (100). Examples abound in patients with sepsis and under other circumstances. The most obvious example is the sepsis-induced loss of cardiomyocyte contractility. High levels of pharmacological support are required to support cardiac ejection, and vascular tone yet cell death is rare. Cardiac performance is analogous to that seen following myocardial infarction, where the remaining cardiomyocytes “hibernate”, presumably to allow recovery (87). A similar response in liver is reflected in low levels in the synthesis of excreted proteins and impaired transformation of both exogenous and endogenous (i.e., bilirubin) toxins (101). In pulmonary cells, this phenomenon has been called “hypoxic conformance” and is characterized in part by internalization, and thus inactivation, of ATPase-linked transmembrane pumps (102). The net result is a failure to clear fluid from the alveolar spaces, resulting in pulmonary edema.

A number of sepsis-induced processes have been attributed to “anti-inflammation” or “immunosuppression” (103). However, these changes might rather reflect “leukocyte hibernation”. Similarly, muscle catabolism is part of the inflammatory process and, under balanced conditions, is followed by anabolism (104, 105). However, decreased catabolism accompanied by failed or insufficient anabolism might reflect “muscle hibernation.”

Cellular hibernation in renal epithelial cells would be consistent with the low levels of cell death observed in septic patients with AKI (106). With rapid recovery, the net effect would be preservation of renal function for the recovery phase. However, prolonged inhibition of energy-requiring functions, such as reduced transcellular electrolyte transport, impaired secretion of potential toxins, and limited generation of essential circulating ions such as bicarbonate and ammonium, would diminish survival. It is possible that early institution of current or future therapeutic approaches could prevent the systemic effects that would result from a reduction in available energy resources with a reprioritization of renal function. Thus, it is essential that a method for determining when limited renal activity becomes maladaptive be developed.

Question 5. What are the mitochondria-based therapeutic targets and opportunities for intervention?

In patients with sepsis, alterations in cellular metabolism can develop as a consequence of inflammation, cytokine signaling, tissue hypoxia, catecholamine stimulation, altered insulin signaling, and other factors. Disordered metabolism in sepsis can disrupt glucose metabolism, resulting in augmented glycolytic flux and increased lactate production, even in the absence of cellular hypoxia. It can also disrupt lipid metabolism, resulting in the generation of inflammatory lipid mediators that contribute to organ dysfunction. Altered metabolism can also result in the generation of metabolic intermediates that affect intracellular signaling pathways and thereby alter cell function. Finally, metabolic reprogramming can alter the availability of cofactors involved in post-translational modifications of proteins. This can affect signaling pathways and also induce epigenetic changes by affecting the post-translational modification of histone proteins. Mitochondria are centrally involved in cellular metabolism, through their energy production, ROS generation/oxidant signaling, and their ability to interconvert biomolecules through the tricarboxylic acid (TCA) cycle (107). The metabolic disruptions observed in tissues during sepsis show similarities to the patterns observed in other diseases, so it is possible that treatments for those conditions might also be useful in sepsis.

For example, increases in circulating lactate are common in septic patients, even in the apparent absence of tissue hypoxia (108). This may be the result of cytokine or catecholamine signaling, and some studies have observed a correlation between the degree of lactatemia and the severity of sepsis, the outcome, and the response to treatment. This shift to aerobic glycolysis resembles the Warburg effect seen in many cancers (109). The similarities in altered metabolism in cancer and in sepsis raise the question of whether interventions that correct metabolism toward a normal phenotype could be useful therapeutically. Clearly, uncontrolled cell proliferation as seen in cancer is not evident during sepsis. Nevertheless, the increased glycolysis in cancer cells is important for channeling glycolytic intermediates into the pentose phosphate pathway, which generates NADPH needed for cellular antioxidant activity (110). Inhibition of NADPH synthesis causes lethal oxidant stress in tumor cells, and the augmented glucose utilization in sepsis may represent a physiological attempt to manage oxidant stress. Presently, it is not clear whether the increase in aerobic glycolysis in sepsis is a marker of inflammation or an upstream mediator of cellular dysfunction. More information is therefore needed to understand whether throttling the glycolytic flux would confer protection, or alternatively exacerbate the condition by undermining antioxidant capacity. In either case, limited therapeutic options for modifying aerobic glycolysis are currently available.

Septic patients frequently develop hyperglycemia. Insulin can be used to control blood glucose in septic patients although this carries the risk of inducing hypoglycemia (111). The antidiabetic drug metformin decreases gluconeogenesis in the liver and ameliorates hyperglycemia by lessening hepatic glucose release. This effect is mediated by its inhibition of mitochondrial complex I, causing a decrease in ATP that activates AMPK. AMPK is a master regulator of cellular energy flux; it inhibits anabolic, energy-consuming processes while promoting catabolic, energy-producing pathways. In sepsis, AMPK activation might confer protection by attenuating inflammation and inflammatory cytokine expression, by augmenting glucose uptake, or by suppressing the effects of inflammation on endothelium. AMPK is activated by hypoxia- or ischemia-induced bioenergetic crises that decrease ATP levels. However, it is also activated by mild hypoxia which causes release of mtROS signals (112). AMPK has been shown to protect against organ failure and inflammation in mouse models of experimental sepsis (113). Therefore, manipulation of AMPK using available drugs might be therapeutic in sepsis.

As in cancer, metabolic reprogramming in sepsis may affect tissue function by promoting epigenetic changes that shape gene expression during acute illness and long after recovery. Key mechanisms of epigenetic change involve post-translational modifications to histone proteins in chromatin. The most common modifications involve the methylation or acetylation of lysine residues on histones. These modifications can increase or decrease expression of genes by altering the accessibility of specific sites to transcription factors, by creating DNA binding sites on chromatin, and by facilitating protein–protein interactions that modify transcriptional activation or repression. In sepsis, it is well-established that extracellular signals induced by the inflammatory cytokines can alter cellular function. Similarly, intracellular metabolic reprogramming may lead to epigenetic changes through alterations in the availability of cofactors needed for the post-translational modification of histone proteins. In cancer and other diseases, epigenetic modifications to histones proteins can alter the cellular phenotype in terms of proliferation, survival, and metastatic behavior. Conceivably, altered metabolic pathway functions in sepsis and critical illness could induce epigenetic modifications and thereby shape organ system function during the disease and long after.

Lysine residues on histone tails are acetylated by histone acetyltransferases (HAT) that use acetyl CoA, an important metabolic intermediate, as a cofactor. In mitochondria, acetyl CoA generated by pyruvate dehydrogenase is condensed with oxaloacetate to generate citrate in the TCA cycle. Citrate can then be exported to the cytosol where acetyl CoA and oxaloacetate are released by ATP citrate lyase. Thus, the mitochondria function as an important source of acetyl CoA needed for HAT activity. Reversal of acetylation is achieved by histone deacetylases (HDAC), some of which (sirtuins and class III) use NAD+ as a cofactor. Metabolic reprogramming in sepsis and cancer can alter NAD+ levels in the cytosol as a consequence of altered glycolytic and/or mitochondrial function, thereby altering the availability of this cofactor for HDAC activity. HDACs also regulate acetylation of cytosolic proteins, and can thereby affect cells signaling and protein trafficking. HDAC inhibitors have long been used as psychotropic medications, and recently have been used in the treatment of cancers and lymphoma. Recent emerging data suggest that HDAC inhibitors may be protective in animal models of sepsis (114). HDACs act on multiple targets, so it will be difficult to identify any protective mechanisms. Nevertheless, HDAC function remains an intriguing target of potential therapeutic interventions.

Lysines are also modified by DNA methyl transferases (DMAT) that use S-adenosyl methionine as a methyl-donating cofactor, and by histone demethylases that use 2-oxoglutarate and O2 as substrates. Sepsis-induced disruptions in signaling or metabolism may therefore modify chromatin remodeling by altering the availability of cofactors, and also by altering the expression, activity, or protein–protein interactions involved in the regulation of histone methylation. Demethylase activity could be inhibited by cellular hypoxia and/or alterations in mitochondrial production of 2-oxoglutarate in sepsis. The DMAT inhibitor, 5-aza 2-deoxycytidine, has been used for the treatment of myelodysplastic syndromes and leukemias. Interesting emerging data suggest that this drug may confer protection against acute lung injury in a rodent sepsis model.

Many cancer chemotherapeutic agents induce significant tissue injury in the heart, lungs, kidneys, and the central nervous system, and would be unsuitable for the treatment of sepsis. However, the examples presented above suggest that some agents used for the treatment of diverse disorders might be useful in the treatment of acute sepsis. Clearly, additional studies are necessary to explore these possibilities.

ADQI XIV Workgroup

Nishkantha Arulkumaran

Vincenzo Cantaluppi

Lakhmir S. Chawla

Daniel de Backer

Clifford S. Deutschman

Mitchell P. Fink

Stuart L. Goldstein

Hernando Gómez

Alonso Gómez

Glenn Hernandez

Can Ince

John A. Kellum

John C. Marshall

Philip R. Mayeux

Patrick Murray

Trung C. Nguyen

Steven M. Opal

Gustavo Ospina-Tascón

Didier Payen

Michael R. Pinsky

Thomas Rimmelé

Paul T. Schumacker

Brian S. Zuckerbraun


Mitochondria, sepsis, inflammation, mitophagy, apoptosis, biogenesis.


1. Osbakken M, Mayevsky A. Multiparameter monitoring and analysis of in vivo ischemic and hypoxic heart. J Basic Clin Physiol Pharmacol 1996; 7 2:97–113.
2. Stidwill RP, Rosser DM, Singer M. Cardiorespiratory, tissue oxygen and hepatic NADH responses to graded hypoxia. Intensive Care Med 1998; 24 11:1209–1216.
3. Kraut A, Barbiro-Michaely E, Mayevsky A. Differential effects of norepinephrine on brain and other less vital organs detected by a multisite multiparametric monitoring system. Med Sci Monit 2004; 10 7:BR215–BR220.
4. Clavijo JA, van Bastelaar J, Pinsky MR, Puyana JC, Mayevsky A. Minimally invasive real time monitoring of mitochondrial NADH and tissue blood flow in the urethral wall during hemorrhage and resuscitation. Med Sci Monit 2008; 14 9:BR175–BR182.
5. From AH, Ugurbil K. Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles. Am J Physiol Cell Physiol 2011; 301 1:C1–C11.
6. Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A 2005; 102 3:808–813.
7. Kariman K, Hempel FG, Jobsis FF. In vivo comparison of cytochrome aa3 redox state and tissue PO2 in transient anoxia. J Appl Physiol Respir Environ Exerc Physiol 1983; 55 4:1057–1063.
8. Guery BP, Mangalaboyi J, Menager P, Mordon S, Vallet B, Chopin C. Redox status of cytochrome a,a3: a noninvasive indicator of dysoxia in regional hypoxic or ischemic hypoxia. Crit Care Med 1999; 27 3:576–582.
9. Forget AP, Mangalaboyi J, Mordon S, Guery B, Vallet B, Fourrier F, Chopin C. Escherichia coli endotoxin reduces cytochrome aa3 redox status in pig skeletal muscle. Crit Care Med 2000; 28 10:3491–3497.
10. Cairns CB, Moore FA, Haenel JB, Gallea BL, Ortner JP, Rose SJ, Moore EE. Evidence for early supply independent mitochondrial dysfunction in patients developing multiple organ failure after trauma. J Trauma 1997; 42 3:532–536.
11. Mik EG, Stap J, Sinaasappel M, Beek JF, Aten JA, van Leeuwen TG, Ince C. Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX. Nat Methods 2006; 3 11:939–945.
12. Protti A, Fortunato F, Caspani ML, Pluderi M, Lucchini V, Grimoldi N, Solimeno LP, Fagiolari G, Ciscato P, Zella SM, et al. Mitochondrial changes in platelets are not related to those in skeletal muscle during human septic shock. PloS One 2014; 9 5:e96205.
13. Sjovall F, Morota S, Hansson MJ, Friberg H, Gnaiger E, Elmer E. Temporal increase of platelet mitochondrial respiration is negatively associated with clinical outcome in patients with sepsis. Crit Care 2010; 14 6:R214.
14. Weiss SL, Selak MA, Tuluc F, Perales Villarroel J, Nadkarni VM, Deutschman CS, Becker LB. Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock. Pediatr Crit Care Med 2015; 16 1:e4–e12.
15. Carchman EH, Whelan S, Loughran P, Mollen K, Stratamirovic S, Shiva S, Rosengart MR, Zuckerbraun BS. Experimental sepsis-induced mitochondrial biogenesis is dependent on autophagy, TLR4, and TLR9 signaling in liver. FASEB J 2013; 27 12:4703–4711.
16. Boekstegers P, Weidenhofer S, Pilz G, Werdan K. Peripheral oxygen availability within skeletal muscle in sepsis and septic shock: comparison to limited infection and cardiogenic shock. Infection 1991; 19:317–323.
17. Sair M, Etherington PJ, Peter Winlove C, Evans TW. Tissue oxygenation and perfusion in patients with systemic sepsis. Crit Care Med 2001; 29:1343–1349.
18. Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 2010; 182:745–751.
19. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360:219–223.
20. Vanasco V, Magnani ND, Cimolai MC, Valdez LB, Evelson P, Boveris A, Alvarez S. Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential. J Bioenerg Biomembr 2012; 44:243–252.
21. Cuzzocrea S, Mazzon E, Di Paola R, Esposito E, Macarthur H, Matuschak GM, Salvemini D. A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock. J Pharmacol Exp Ther 2006; 319:73–81.
22. Beltran B, Orsi A, Clementi E, Moncada S. Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 2000; 129:953–960.
23. Boulos M, Astiz ME, Barua RS, Osman M. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med 2003; 31:353–358.
24. Levy RJ, Vijayasarathy C, Raj NR, Avadhani NG, Deutschman CS. Competitive and noncompetitive inhibition of myocardial cytochrome c oxidase in sepsis. Shock 2004; 21:110–114.
25. Piel DA, Gruber PJ, Weinheimer CJ, Courtois MR, Robertson CM, Coopersmith CM, Deutschman CS, Levy RJ. Mitochondrial resuscitation with exogenous cytochrome c in the septic heart. Crit Care Med 2007; 35:2120–2127.
26. Piel DA, Deutschman CS, Levy RJ. Exogenous cytochrome C restores myocardial cytochrome oxidase activity into the late phase of sepsis. Shock 2008; 29:612–616.
27. Verma R, Huang Z, Deutschman CS, Levy RJ. Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis. Crit Care Med 2009; 37:1397–1402.
28. Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol 2004; 286:R491–R497.
29. Fredriksson K, Flaring U, Guillet C, Wernerman J, Rooyackers O. Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers. Acta Anaesthesiol Scand 2009; 53:299–304.
30. Trumbeckaite S, Opalka JR, Neuhof C, Zierz S, Gellerich FN. Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function. Eur J Biochem 2001; 268:1422–1429.
31. Protti A, Fortunato F, Caspani ML, Pluderi M, Lucchini V, Grimoldi N, Solimeno LP, Fagiolari G, Ciscato P, Zella SM, et al. Mitochondrial changes in platelets are not related to those in skeletal muscle during human septic shock. PLoS One 2014; 9:e96205.
32. Echtenacher B, Freudenberg MA, Jack RS, Mannel DN. Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis. Infect Immun 2001; 69:7271–7276.
33. Remick D, Manohar P, Bolgos G, Rodriguez J, Moldawer L, Wollenberg G. Blockade of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal ligation and puncture. Shock 1995; 4:89–95.
34. Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 2000; 13:110–116.
35. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008; 30:393–402.
36. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 1998; 95:11715–11720.
37. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000; 275:25130–25138.
38. Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GR, Chandel NS. The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 2007; 177:1029–1036.
39. Al-Mehdi AB, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, Pastukh VV, Alexeyev MF, Gillespie MN. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci Signal 2012; 5:ra47.
40. Waypa GB, Chandel NS, Schumacker PT. Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 2001; 88:1259–1266.
41. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011; 469:221–225.
42. Mao K, Chen S, Chen M, Ma Y, Wang Y, Huang B, He Z, Zeng Y, Hu Y, Sun S, et al. Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Cell Res 2013; 23:201–212.
43. Emre Y, Hurtaud C, Nubel T, Criscuolo F, Ricquier D, Cassard-Doulcier AM. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem J 2007; 402:271–278.
44. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472:476–480.
45. Chandel NS, Schumacker PT, Arch RH. Reactive oxygen species are downstream products of TRAF-mediated signal transduction. J Biol Chem 2001; 276:42728–42736.
46. Borutaite V, Budriunaite A, Brown GC. Reversal of nitric oxide-, peroxynitrite- and S-nitrosothiol-induced inhibition of mitochondrial respiration or complex I activity by light and thiols. Biochim Biophys Acta 2000; 1459:405–412.
47. Alvarez S, Boveris A. Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia. Free Radic Biol Med 2004; 37:1472–1478.
48. Quoilin C, Mouithys-Mickalad A, Lecart S, Fontaine-Aupart MP, Hoebeke M. Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury. Biochim Biophys Acta 2014; 1837:1790–1800.
49. Zapelini PH, Rezin GT, Cardoso MR, Ritter C, Klamt F, Moreira JC, Streck EL, Dal-Pizzol F. Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 2008; 8:211–218.
50. Patil NK, Parajuli N, MacMillan-Crow LA, Mayeux PR. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am J Physiol 2014; 306:F734–F743.
51. Seija M, Baccino C, Nin N, Sanchez-Rodriguez C, Granados R, Ferruelo A, Martinez-Caro L, Ruiz-Cabello J, de Paula M, Noboa O, et al. Role of peroxynitrite in sepsis-induced acute kidney injury in an experimental model of sepsis in rats. Shock 2012; 38:403–410.
52. Kantrow SP, Tatro LG, Piantadosi CA. Oxidative stress and adenine nucleotide control of mitochondrial permeability transition. Free Radic Biol Med 2000; 28:251–260.
53. Simbula G, Glascott PA Jr, Akita S, Hoek JB, Farber JL. Two mechanisms by which ATP depletion potentiates induction of the mitochondrial permeability transition. Am J Physiol 1997; 273:C479–C488.
54. Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL. Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 1993; 268:13791–13798.
55. Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol 2005; 174:5110–5118.
56. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230–1251.
57. Ekbal NJ, Dyson A, Black C, Singer M. Monitoring tissue perfusion, oxygenation, and metabolism in critically ill patients. Chest 2013; 143:1799–1808.
58. Mik EG, Stap J, Sinaasappel M, Beek JF, Aten JA, van Leeuwen TG, Ince C. Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX. Nat Methods 2006; 3:939–945.
59. Sjovall F, Morota S, Hansson MJ, Friberg H, Gnaiger E, Elmer E. Temporal increase of platelet mitochondrial respiration is negatively associated with clinical outcome in patients with sepsis. Crit Care 2010; 14:R214.
60. Weiss SL, Selak MA, Tuluc F, Perales Villarroel J, Nadkarni VM, Deutschman CS, Becker LB. Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock. Pediatr Crit Care Med 2015; 16:e4–e12.
61. Whelan SP, Zuckerbraun BS. Mitochondrial signaling: forwards, backwards, and in between. Oxid Med Cell Longev 2013; 2013:351613.
62. Vogtle FN, Meisinger C. Sensing mitochondrial homeostasis: the protein import machinery takes control. Dev Cell 2012; 23:234–236.
63. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 2012; 337:587–590.
64. Pellegrino MW, Nargund AM, Haynes CM. Signaling the mitochondrial unfolded protein response. Biochim Biophys Acta 2013; 1888:410–416.
65. Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science 2012; 337:1062–1065.
66. Chan DC. Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet 2012; 46:265–287.
67. Gonzalez AS, Elguero ME, Finocchietto P, Holod S, Romorini L, Miriuka SG, Peralta JG, Poderoso JJ, Carreras MC. Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis. Free Radic Res 2014; 48:769–783.
68. Deretic V, Levine B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 2009; 5:527–549.
69. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 2007; 7:767–777.
70. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6:463–477.
71. Mao K, Klionsky DJ. Mitochondrial fission facilitates mitophagy in Saccharomyces cerevisiae. Autophagy 2013; 9:1900–1901.
72. Watanabe E, Muenzer JT, Hawkins WG, Davis CG, Dixon DJ, McDunn JE, Brackett DJ, Lerner MR, Swanson PE, Hotchkiss RS. Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Lab Invest 2009; 89:549–561.
73. Carchman EH, Rao J, Loughran PA, Rosengart MR, Zuckerbraun BS. Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice. Hepatology 2011; 53:2053–2062.
74. Hosokawa S, Koseki H, Nagashima M, Maeyama Y, Yomogida K, Mehr C, Rutledge M, Greenfeld H, Kaneki M, Tompkins RG, Martyn JA, Yasuhara SE. Title efficacy of phosphodiesterase 5 inhibitor on distant burn-induced muscle autophagy, microcirculation, and survival rate. Am J Physiol 2013; 304:E922–E933.
75. Gunst J, Derese I, Aertgeerts A, Ververs EJ, Wauters A, Van den Berghe G, Vanhorebeek I. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit Care Med 2014; 41:182–194.
76. Zhang X, Howell GM, Guo L, Collage RD, Loughran PA, Zuckerbraun BS, Rosengart MR. CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. J Immunol 2014; 193:2405–2415.
77. Howell GM, Gomez H, Collage RD, Loughran P, Zhang X, Escobar DA, Billiar TR, Zuckerbraun BS, Rosengart MR. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PLoS One 2013; 8:e69520.
78. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011; 469:221–225.
79. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011; 12:222–230.
80. Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 2010; 182:745–751.
81. Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O. Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Physiol 2006; 291:E1044–E1050.
82. Haden DW, Suliman HB, Carraway MS, Welty-Wolf KE, Ali AS, Shitara H, Yonekawa H, Piantadosi CA. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med 2007; 176:768–777.
83. Carchman EH, Whelan S, Loughran P, Mollen K, Stratamirovic S, Shiva S, Rosengart MR, Zuckerbraun BS. Experimental sepsis-induced mitochondrial biogenesis is dependent on autophagy, TLR4, and TLR9 signaling in liver. FASEB J 2013; J 27:4703–4711.
84. Mannam P, Shinn AS, Srivastava A, Neamu RF, Walker WE, Bohanon M, Merkel J, Kang MJ, Dela Cruz CS, Ahasic AM, et al. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am J Physiol 2014; 306:L604–L619.
85. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014; 5:66–72.
86. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 2004; 364:545–548.
87. Levy RJ, Piel DA, Acton PD, et al. Evidence of myocardial hibernation in the septic heart. Crit Care Med 2005; 33:2752–2756.
88. Schumacker PT, Gillespie MN, Nakahira K, et al. Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol 2014; 306:L962–L974.
89. Schumacker PT. Lung cell hypoxia Role of mitochondrial reactive oxygen species signaling in triggering responses. Proc Am Thorac Soc 2011; 8:477–484.
90. Piantadosi CA, Suliman HB. Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes. Biochim Biophys Acta 2012; 1820:532–541.
91. Kaasik A, Kuum M, Joubert F, et al. Mitochondria as a source of mechanical signals in cardiomyocytes. Cardiovasc Res 2010; 87:83–91.
92. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, et al. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial function. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992; 267:5317–5323.
93. Kantrow SP, Taylor DE, Carraway MS, et al. Oxidative metabolism in in rat hepatocytes and mitochondria during sepsis. Arch Biochem Biophys 1997; 345:278–288.
94. Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132–141.
95. Brouillette MJ, Ramakrishnan PS, Wagner VM, et al. Strain-dependent oxidant release in auricular cartilage originates from mitochondria. Biomech Model Mechanobiol 2014; 13:565–572.
96. Wolff KJ, Ramakrishnan PS, Brouillette MJ, et al. Mechanical stress and ATP synthesis are coupled by mitochondrial oxidants in articular cartilage. J Orthop Res 2013; 2:191–196.
97. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5:343–354.
98. Semenza GL. Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2010; 2:336–361.
99. Huang LE, Gu J, Schau M, et al. Regulation of hypoxia-inducible factor 1a is mediated by an O2-dependent degradation domain via the ubiquitin-proteosome pathway. Proc Natl Acad Sci U S A 1998; 95:7987–7992.
100. Budinger GR, Duranteau J, Chandel NS, et al. Hibernation during hypoxia in cardiomyocytes. Role of mitochondria as the O2 sensor. J Biol Chem 1998; 273:3320–3326.
101. Kim PK, Chen J, Andrejko KM, et al. Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats. Shock 2000; 14:176–181.
102. Vadasz I, Dada LA, Briva A, et al. AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and humans by promoting Na,K-ATPase endocytosis. J Clin Invest 2008; 118:752–762.
103. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13:260–268.
104. Semmler A, Okulla T, Kaiser M, et al. Long-term neuromuscular sequelae of critical illness. J Neurol 2013; 260:151–157.
105. Alamdari N, Smith IJ, Aversa Z, et al. Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle. Am J Physiol 2010; 299:R509–R520.
106. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2004; 348:138–150.
107. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 2014; 14:709–721.
108. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014; 371:2309–2319.
109. Hamanaka RB, Chandel NS. Targeting glucose metabolism for cancer therapy. J Exp Med 2012; 209:211–215.
110. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324:1029–1033.
111. Andersen SK, Gjedsted J, Christiansen C, Tonnesen E. The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol 2004; 75:413–421.
112. Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, Schumacker PT. Hypoxia triggers AMPK activation through ROS-mediated activation of CRAC channels. Mol Cell Biol 2011; 31:3531–3545.
113. Escobar DA, Botero-Quintero AM, Kautza BC, Luciano J, Loughran P, Darwiche S, Rosengart MR, Zuckerbraun BS, Gomez H. Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J Surg Res 2015; 194:262–272.
114. Takebe M, Oishi H, Taguchi K, Aoki Y, Takashina M, Tomita K, Yokoo H, Takano Y, Yamazaki M, Hattori Y. Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis. J Surg Res 2014; 187:559–570.

Consensus; critical illness; mitochondria sepsis

© 2016 by the Shock Society