sepsis is the systemic inflammatory response to infection and represents a major cause of morbidity and mortality in patients admitted to intensive care units ( icus ) . however , despite decades of research , the pathophysiology of sepsis remains incompletely understood . a critical limitation of tissue oxygen delivery due to macrocirculatory or microcirculatory failure may play a role , especially in the early phase of the disease process before resuscitation has been initiated .
nonetheless , a growing body of evidence suggests that multiple organ failure ( mof ) may develop during sepsis mainly as a consequence of impaired cellular oxygen utilization .
supportive data in patients include the following findings : total body oxygen consumption falls progressively with increasing severity of sepsis ; skeletal muscle tissue oxygen tension is abnormally high but normalizes during the recovery phase ; necrotic and apoptotic cell death is minimal , if it occurs at all , in most dysfunctioning organs ; and organs with limited regenerative capabilities , such as kidney , are usually able to recover to such an extent that long - term support is usually not needed .
sepsis - induced mof may thus be related to a potentially reversible impairment in cellular function rather than any permanent structural damage .
cellular energy production depends on three interconnected pathways : glycolysis within the cytoplasm , the krebs cycle and the electron transport chain within the mitochondria ( figure 1 ) .
glycolysis is a sequence of reactions that degrade glucose to pyruvate . in the presence of oxygen , pyruvate and other fuel molecules such as fatty acids and amino acids
enter the mitochondria , where they are completely oxidized within the krebs cycle . the reduced nicotinamide
( nadh ) and flavin ( fadh2 ) adenine dinucleotides transfer electrons to the respiratory enzyme complexes located in the inner mitochondrial membrane ( electron transport chain ) for the process of atp generation by oxidative phosphorylation .
the electrons then flow via coenzyme q ( ubiquinone ) to complex iii , and are then transported via cytochrome c to reach complex iv ( cytochrome oxidase ) . at this final stage
electron transfer through complexes i , iii and iv generates a proton gradient across the inner mitochondrial membrane that is used by atp synthase ( complex v ) to generate energy by phosphorylating adp .
the complete oxidation of one molecule of glucose yields 3036 molecules of atp , two of which come from glycolysis and two from the krebs cycle .
however , when oxygen is lacking , pyruvate can no longer be further oxidized within the mitochondria and is thus metabolized to lactate within the cytoplasm .
glycolysis represents a much less efficient metabolic pathway compared with the krebs cycle and oxidative phosphorylation , because there is net synthesis of only two molecules of atp per molecule of glucose . because mitochondria utilize more than 90% of total body oxygen consumption to produce atp , the abnormalities in oxygen consumption described during sepsis are likely to be associated with evidence of mitochondrial dysfunction .
studies conducted during the early phase of sepsis ( within the first few hours ) have produced conflicting results .
nonetheless , mitochondrial structure and function were consistently shown to be impaired in a severity - dependent manner in animal models lasting at least 1216 hours . of note
, atp levels were variably affected , depending on the balance between energy production and consumption , the model and possibly the tissue under investigation . in septic shock patients
studied within 24 hours of icu admission , the degree of skeletal muscle mitochondrial dysfunction was associated with the severity of the disease . in this work ,
tissue atp levels were significantly lower in nonsurvivors than in an orthopaedic surgical control population , but they were maintained in those who survived sepsis .
a reduction in energy consumption implies a reduction in cellular metabolism , which manifests clinically as organ dysfunction . rather than being viewed negatively as ' failure ' , an alternative paradigm may be advanced whereby this metabolic shutdown represents an adaptive cellular strategy . in the face of persisting mitochondrial dysfunction and reduced atp production ,
the cell may shift its focus to survival rather than aiming to continue normal functioning .
nitric oxide ( no ) , reactive oxygen species and other inflammatory mediators are produced in excess and can directly inhibit mitochondrial respiration .
no competes with oxygen in binding to cytochrome oxidase ( complex iv ) , thereby decreasing the activity of the enzyme .
superoxide will react with no to generate peroxynitrite and other nitrogen species that are able to alter the structure and function of several other mitochondrial proteins , notably complex i .
early cellular hypoxia may favour the competitive no - mediated inhibition of cytochrome oxidase , contributing to the earlier , if not greater , development of mitochondrial dysfunction .
endocrine changes that occur during sepsis are also likely to play a role . among others , thyroid and sex hormones , insulin , glucocorticoids and leptin
positively modulate mitochondrial energy production , protein synthesis and biogenesis [ 13 - 17 ] .
increased incidences of the low tri - iodothyronine ( t3 ) syndrome , hypogonadism , insulin resistance , adrenal insufficiency and decreased circulating leptin levels in nonsurvivors compared with survivors have been reported during prolonged sepsis and critical illness .
accordingly , depletion of respiratory complex proteins has been described in the diaphragm in a rat model of sepsis .
a further mechanism could be represented by the down - regulated synthesis of new mitochondrial protein . in human volunteers , administration of bacterial endotoxin decreased blood leucocyte expression of mitochondrial respiratory chain complexes and atp synthase genes .
assuming that the pathogenesis of mof during sepsis is contingent on development of mitochondrial dysfunction and cellular energetic failure , recovery is likely to occur when damaged organelles are repaired or replaced .
preliminary results have shown an association between progressive improvement in mitochondrial respiration and organ function in patients who survive their episode of septic shock .
strategies aimed at preventing or reversing mitochondrial dysfunction and cellular energetic failure may thus represent a new therapeutic option in the treatment of sepsis ( figure 2 ) .
mitochondrial dysfunction in sepsis can occur even with aggressive fluid resuscitation   and adequate tissue oxygenation .
derangement in liver metabolism possibly due to mitochondrial damage was recently reported in a hyperdynamic , normotensive , mechanically ventilated , antibiotic - treated septic animal model , despite preserved microvascular perfusion .
nonetheless , early cellular hypoxia can further limit aerobic production of atp and contribute to the development of energy failure .
optimization of oxygen delivery can ameliorate cellular energetic failure provided that mitochondria retain their ability to produce energy .
patients with severe sepsis or septic shock whose global oxygen delivery was optimized early after admission to an emergency room experienced better outcomes than did conventionally managed patients .
conversely , no benefit   or even harm   was reported when a similar approach was adopted after admission to icu , when organ failure had already become established .
the same intervention , performed at different time points , had very different clinical impacts . in the early phase , when the cellular energetic machinery is still likely to be functional and oxygen supply may represent a limiting factor , reversal of tissue hypoxia may ameliorate the impending cellular energetic failure and reduce the incidence / severity of organ dysfunction . in a later phase ,
when mitochondrial damage has occurred and the cell has become intrinsically unable to utilize oxygen to produce atp , a similar strategy may not provide any benefit .
lack of improvement in oxygen consumption despite a re - established oxygen supply has been associated with unfavourable outcomes in patients with sepsis syndrome or septic shock .
hyperglycaemia and insulin resistance are common among critically ill patients and represent an additional potential threat to mitochondrial integrity .
acute hyperglycaemia can dramatically increase the production of reactive oxygen species in normal bovine aortic endothelial cells .
maintenance of normo - glycaemia with intensive insulin therapy during critical illness has been demonstrated to preserve hepatocyte mitochondrial ultrastructure and function   and improve outcome in both medical and surgical intensive care patients .
reactive oxygen and nitrogen species are over - produced during sepsis , whereas mitochondrial antioxidants ( reduced glutathione and manganese superoxide ) are depleted .
the membrane permeable glutathione ethyl ester can protect complex i from oxidative and nitrosative damage in an early phase .
manganese - based superoxide dismutase mimetics may exert a similar protective effect , scavenging superoxide anions and preventing them from further reacting with no to generate peroxynitrite within the mitochondria .
once permanent mitochondrial dysfunction has developed , cellular optimization of any residual ability to produce energy and/or reduce metabolic requirements may prevent the atp level from dropping below the threshold that stimulates initiation of cell death pathways .
electron donors that are able to ' bypass ' defective components of the respiratory chain may help in attaining the former objective . within the inner mitochondrial membrane , complex ii works in parallel with complex i , albeit to a lesser extent , transferring electrons from fadh2 produced during the oxidation of succinate to coenzyme q. unlike complex i , the activity of complex ii is relatively preserved during sepsis .
when complex i is inhibited , the administration of succinate may increase electron flow through the respiratory chain and thus increase generation of atp , provided that any inhibition of the electron transport chain distal to complex ii has not become rate - limiting .
preliminary data from our laboratory confirm this action . in two different animal models of sepsis ,
the infusion of succinate dimethyl ester prevented the fall in liver atp content   and prolonged survival time .
another possible strategy that could be pursued in the face of a severe and extended impairment in mitochondrial energy production is to reduce cellular energetic expenditure . hibernating and aestivating animals reduce their metabolic rate in the face of climate change or drought .
similarly , oxygen - conforming organisms such as turtles and frogs can tolerate prolonged periods of hypoxia by suppressing atp turnover .
humans do not hibernate or aestivate and have only a limited tolerance to inadequate oxygenation .
nonetheless , patients with chronic coronary artery disease frequently develop a myocardial contractile dysfunction  termed myocardial hibernation  that may represent an adaptive response to ischaemia , rather than depend on an ongoing energetic deficit , which will recover on restoration of adequate perfusion .
carbon monoxide and no may mediate the active decrease in energy demand that occurs in cells that lack oxygen . the natural peptide ' hibernation induction trigger ' , its synthetic analogue [ d - ala , d - leu ] enkephalin ( dadle ) and other -opioids can also reduce cellular metabolism and protect organs against ischaemia .
rapid induction of profound cerebral hypothermia in animals that do not normally hibernate may guarantee protection during prolonged cardio - circulatory arrest .
mice exposed to hydrogen sulphide experience a dramatic decrease in their metabolic rate : within 6 hours , oxygen consumption and carbon dioxide production drop by around 90% , and body core temperature approaches that of the environment .
such a suspended animation - like state fully reverses when the hydrogen sulphide is discontinued , without any permanent behavioural or functional damage .
it is conceivable that , even during sepsis , induced hibernation may protect the organism from prolonged energetic failure and enable faster recovery on resolution of the inflammatory insult .
for example , the hyperthermic response to infection activates the expression of cytoprotective heat shock proteins and may therefore be considered beneficial .
premature stimulation of cellular metabolism before mitochondria have regained their ability to respond adequately in terms of energy production may lead to cellular compromise .
examples of harmful therapeutic approaches that may be invoked are the use of high - dose dobutamine , thyroxine   and growth hormone .
repair and replacement of damaged mitochondria are probably controlled at a transcriptional level , but proximal steps in the signalling pathway still need to be elucidated . no was recently suggested to play a major role .
long - term exposure to a low concentration of the gas triggered expression of transcriptional factors that regulate mito - chondrial proliferation and significantly increased mito - chondrial mass in different cells in culture .
the large quantity synthesized by the inducible isoform of nitric oxide synthase ( nos ) during the acute inflammatory response to sepsis blocks mitochondrial respiration and can be cytotoxic . on the other hand ,
the smaller amounts of no produced by the specific constitutive endothelial nos may trigger mitochondrial biogenesis in a later phase .
taken together , these results suggest that recovery from mito - chondrial dysfunction may depend on a no - dependent signalling pathway
. specific inhibition of inducible nos during sepsis may represent a potential therapeutic strategy [ 52 - 55 ] , although dose selection will be critical .
this is pertinent to the dose - related increase in mortality reported in a phase iii trial of a nonspecific nos inhibitor in septic shock patients .
indeed , the overall negative outcome of this study camouflages the survival benefit seen with low doses .
in contrast to the acute response , persistently low circulating levels of t3 during the prolonged phase of critical illness may be due to neuroendocrine dysfunction .
replacement hormonal therapy given at the right time , when cells have regained the ability to both restore mitochondrial activity and increase metabolic rate , may beneficially arouse the cell and promote earlier organ recovery .
however , as described above , thyroxine supplementation may prove dangerous , and so the right conditions must be in place .
other hormones that could be considered in the treatment of sepsis are leptin and oestrogen .
it regulates food intake and energy balance to maintain constancy of total body fat mass . in diabetic fatty rats ,
ectopic hyperleptinaemia triggered mitochondrial proliferation , transforming white adipocytes into mitochondria - rich , fat - oxidizing cells .
administration of oestrogen or antiandrogen agents after trauma / haemorrhage also increased mitochondrial enzyme activities , protein synthesis and atp levels relative to those in sham - operated controls .
this is a reversible , low - growth state well recognized in mycobacteria such as mycobacterium tuberculosis .
micrococcus luteus can be aroused from its quiescent phase by an endogenous protein named ' resuscitation promoting factor ' .
as mitochondria descend from a bacterial endosymbiont , the identification and application of a similar protein that can specifically stimulate mitochondrial activity may well yield beneficial results .
mitochondrial dysfunction occurs during sepsis and may play a major role in the development of mof .
prevention and correction of mitochondrial dysfunction and cellular energetic failure represent novel strategies that may improve clinical outcomes of septic patients .
timing of any intervention appears to be critical and the possibly adaptive role of some changes currently viewed as pathological must be considered .
the regulated induction of a hypometabolic state resembling hibernation may help the cell in facing a reduced capacity to generate energy .
the stimulation of mitochondrial activity and biogenesis during the late phase of sepsis may accelerate the recovery process .
this increasing insight into underlying mechanisms promises to be an exciting era of novel therapeutic developments .
fadh2 = flavin adenine dinucleotide , reduced ; icu = intensive care unit ; mof = multiple organ failure ; nadh = nicotinamide adenine dinucleotide , reduced ; no = nitric oxide ; nos = nitric oxide synthase ; t3 = tri - iodothyronine .
ms receives research funding from the medical research council and wellcome trust to undertake basic science research on mitochondria .
electrons donated from nadh and fadh2 pass down the electron transport chain with oxygen being the terminal acceptor at complex iv .
this movement of electrons results in a shift of protons across the inner mitochondrial membrane , generating the energy necessary for atp synthase to produce atp from adp .
fadh2 , flavin adenine dinucleotide , reduced ; nadh , nicotinamide adenine dinucleotide , reduced .
 the pathogenesis of sepsis - induced multiple organ failure may crucially depend on the development of mitochondrial dysfunction and consequent cellular energetic failure . according to this hypothesis 
 , interventions aimed at preventing or reversing mitochondrial damage may have major clinical relevance , although the timing of such interventions will be critical to both ensuring benefit and avoiding harm . 
 early correction of tissue hypoxia , strict control of glycaemia , and modulation of oxidative and nitrosative stress may afford protection during the initial , acute systemic inflammatory response . 
 the regulated induction of a hypometabolic state resembling hibernation may protect the cells from dying once energy failure has developed , allowing the possibility of functional recovery . 
 repair of damaged organelles through stimulation of mitochondrial biogenesis and reactivation of cellular metabolism may accelerate resolution of the multiple organ failure syndrome . 
Introduction
Prevention and early reversal of mitochondrial dysfunction
Prevention of cellular energetic failure in the presence of mitochondrial dysfunction
Resolution of mitochondrial dysfunction: arousal from 'hibernation'
Conclusion
Abbreviations
Competing interests
Figures and Tables