Metabolic Shutdown Research Articles

Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells

L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53-positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients.

Three crucial biological characteristics that’s required for sustaining the livelihood of prokaryote and eukaryote cells

Since living organisms will always form an important part of the ecosystem, it’s imperative to achieve a view on how imbalances cause problems. The one way in attaining this view is by understanding the way in which cells behave in different environments, ranging from the native environment to tested conditions. Cell viability, respiratory events as well as metabolic and nuclear shutdown are some critical events that occur, generally, in prokaryote and eukaryote cells. The distinct characteristics between the two cell types enable an advanced understanding about the occurrence of those features and processes attained during medicinal, and other cell-based studies.

Abstract IA05: Oncogenic signaling pathways and resistance to therapy in T-ALL

Abstract Aberrant NOTCH1 signaling plays a major role in the pathogenesis of over 60% of T-ALLs harboring activating mutations in the NOTCH1 gene. Most notably, oncogenic NOTCH1 has been proposed as a therapeutic target in NOTCH1-mutant leukemias and small molecule γ-secretase inhibitors (GSIs), which effectively block NOTCH activation via inhibition of a critical intramembrane proteolytic cleavage required for NOTCH signaling. However, the clinical development of anti-NOTCH1 therapies in T-ALL has been hampered by the limited and delayed therapeutic response to these drugs, making the identification of highly effective and synergistic drug combinations capable of delivering strong antileukemic responses a top priority in the field. Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, Pten loss and consequent activation of the PI3K pathway induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. These results highlight the fundamental importance of NOTCH1 signaling in the control of leukemia cell metabolism, extend our understanding of the prominent role of PTEN and the PI3K pathway in the control of oncogenic cell growth and provide the basis for the design of new therapeutic strategies targeting cell metabolism for the treatment of T-ALL. Citation Format: Adolfo Ferrando. Oncogenic signaling pathways and resistance to therapy in T-ALL. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA05.

Proteomics Evidence for the Activity of the Putative Antibacterial Plant Alkaloid (-)-Roemerine: Mainstreaming Omics-Guided Drug Discovery.

Discovery of new antibacterials with novel mechanisms is important to counteract the ingenious resistance mechanisms of bacteria. In this connection, omics-guided drug discovery offers a rigorous method in the quest of new antibacterials. (-)-Roemerine is a plant alkaloid that has been reported to possess putative antibacterial activity against Escherichia coli, Bacillus subtilis, and Salmonella typhimurium. The aim of the present study was to characterize the activity of (-)-roemerine in Escherichia coli TB1 using proteomics tools. With (-)-roemerine treatment, we found limited permeability through the outer membrane and repression of transport proteins involved in carbohydrate metabolism, resulting in poor carbon source availability. The shortfall of intracellular carbon sources in turn led to impaired cell growth. The reduction in the abundance of proteins related to translational machinery, amino acid biosynthesis, and metabolism was accompanied by a nutrient-limited state. The latter finding could suggest a metabolic shutdown in E. coli cells. High osmolarity was clearly not one of the reasons of bacterial death by (-)-roemerine. These observations collectively attest to the promise of plant omics and profiling of putative drug candidates using proteomics tools. Omics-guided drug discovery deserves greater attention in mainstream pharmacology so as to better understand the plants' medicinal potentials.

Tools and resources for analyzing gene expression changes in glaucomatous neurodegeneration

Evaluating gene expression changes presents one of the most powerful interrogative approaches to study the molecular, biochemical, and cellular pathways associated with glaucomatous disease pathology. Technologies to study gene expression profiles in glaucoma are wide ranging. Qualitative techniques provide the power of localizing expression changes to individual cells, but are not robust to evaluate differences in expression changes. Alternatively, quantitative changes provide a high level of stringency to quantify changes in gene expression. Additionally, advances in high throughput analysis and bioinformatics have dramatically improved the number of individual genes that can be evaluated in a single experiment, while dramatically reducing amounts of input tissue/starting material. Together, gene expression profiling and proteomics have yielded new insights on the roles of neuroinflammation, the complement cascade, and metabolic shutdown as important players in the pathology of the optic nerve head and retina in this disease.

A comprehensive proteomic analysis of totarol induced alterations in Bacillus subtilis by multipronged quantitative proteomics.

The exact mechanism of action of totarol is still unclear and further investigations are essential to identify the molecular/cellular targets of this potential antimicrobial agent. The present study demonstrates the application of differential proteome to decipher the mechanism of action and molecular targets of totarol in B. subtilis. Our quantitative proteome analysis revealed that totarol induced alterations in the expression levels of 139 proteins (1.5 fold change and ≥2 peptides) in B. subtilis. Findings obtained from this study indicate that totarol treatment leads to metabolic shutdown by repressing the major central metabolic dehydrogenases in B. subtilis. In addition, expression levels of universal chaperone proteins, heme biosynthesis, and ribosomal proteins were found to be altered, which caused the filamentation of the bacteria. To the best of our knowledge, this is the foremost inclusive investigation describing totarol induced alterations in B. subtilis proteome and diverse physiological processes. We anticipate that this in depth proteomic study may contribute to a better understanding of the mode of action of totarol and its primary molecular and cellular targets.

Towards Decrypting Cryptobiosis—Analyzing Anhydrobiosis in the Tardigrade Milnesium tardigradum Using Transcriptome Sequencing

BackgroundMany tardigrade species are capable of anhydrobiosis; however, mechanisms underlying their extreme desiccation resistance remain elusive. This study attempts to quantify the anhydrobiotic transcriptome of the limno-terrestrial tardigrade Milnesium tardigradum.ResultsA prerequisite for differential gene expression analysis was the generation of a reference hybrid transcriptome atlas by assembly of Sanger, 454 and Illumina sequence data. The final assembly yielded 79,064 contigs (>100 bp) after removal of ribosomal RNAs. Around 50% of them could be annotated by SwissProt and NCBI non-redundant protein sequences. Analysis using CEGMA predicted 232 (93.5%) out of the 248 highly conserved eukaryotic genes in the assembly. We used this reference transcriptome for mapping and quantifying the expression of transcripts regulated under anhdydrobiosis in a time-series during dehydration and rehydration. 834 of the transcripts were found to be differentially expressed in a single stage (dehydration/inactive tun/rehydration) and 184 were overlapping in two stages while 74 were differentially expressed in all three stages. We have found interesting patterns of differentially expressed transcripts that are in concordance with a common hypothesis of metabolic shutdown during anhydrobiosis. This included down-regulation of several proteins of the DNA replication and translational machinery and protein degradation. Among others, heat shock proteins Hsp27 and Hsp30c were up-regulated in response to dehydration and rehydration. In addition, we observed up-regulation of ployubiquitin-B upon rehydration together with a higher expression level of several DNA repair proteins during rehydration than in the dehydration stage.ConclusionsMost of the transcripts identified to be differentially expressed had distinct cellular function. Our data suggest a concerted molecular adaptation in M. tardigradum that permits extreme forms of ametabolic states such as anhydrobiosis. It is temping to surmise that the desiccation tolerance of tradigrades can be achieved by a constitutive cellular protection system, probably in conjunction with other mechanisms such as rehydration-induced cellular repair.

Physiology of Desiccation-Sensitive (Recalcitrant) Seeds and the Implications for Cryopreservation

Desiccation-tolerant (orthodox) seeds can survive in the dry state for considerable periods and so can be stored successfully at low water content and subzero temperatures. Orthodox seeds possess a variety of protective processes and mechanisms that confer desiccation tolerance, important among them being metabolic shutdown and intracellular dedifferentiation. In contrast, desiccation-sensitive (recalcitrant) seeds cannot tolerate water loss and so cannot be stored using conventional seed bank conditions. Particularly with respect to storage, recalcitrant seeds do not undergo intracellular dedifferentiation nor any significant metabolic shutdown. Embryos of recalcitrant seeds remain metabolically active, with little or no reduction in extent of the extensive intracellular membranes. At the water content at which they are shed, with the ongoing metabolism in recalcitrant seeds, developmental phenomena grade imperceptibly into those associated with germination. Thus, recalcitrant seeds can be stored intact ...

Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: Supply mismatch in selected ventricular regions?

Takotsubo cardiomyopathy (TCM) or stress-induced cardiomyopathy is an increasingly recognized syndrome characterized by severe regional left ventricular dysfunction in the absence of an explanatory coronary lesion. TCM may lead to lethal complications but is completely reversible if the patient survives the acute phase. The pathogenesis of TCM and the mechanism behind this remarkable recovery are unknown.Plasma levels of catecholamine are elevated in many TCM patients and exogenously administered catecholamine induces TCM-like cardiac dysfunction in both humans and rats. A catecholamine excess increases myocardial metabolic demand by increasing the force of contraction as well as the heart rate, and also alters cardiac depolarization patterns.We propose that an altered spatiotemporal pattern of cardiac contraction and excessive force of contraction may lead to a redistribution of wall stresses in the left ventricle. This redistribution of wall stress causes regional mechanical overload of regions where wall tension becomes disproportionately great and renders these cardiomyocytes “metabolically insufficient”. In other words, these cardiomyocytes experience a demand: supply mismatch on the basis of excessive metabolic demand. In order to prevent the death of these cardiomyocytes and to prevent excessive wall tension from developing in neighboring regions, a protective metabolic shutdown occurs in the affected cardiomyocytes. This metabolic shutdown, i.e., acute down regulation of non-vital cellular functions, serves to protect the affected regions from necrosis and explains the apparently complete recovery observed in TCM. We propose that this phenomenon may share important characteristics with phenomena such as ischemic conditioning, stunning and hibernation. In this manuscript, we discuss our hypothesis in the context of available knowledge and discuss important experiments that would help to corroborate or refute the hypothesis.

Proteomic analysis of Streptomyces coelicolor in response to Ciprofloxacin challenge

Multi-drug tolerance is an important phenotypic property that complicates treatment of infectious diseases and reshapes drug discovery. Hence a systematic study of the origins and mechanisms of resistance shown by microorganisms is imperative. Since soil-dwelling bacteria are constantly challenged with a myriad of antibiotics, they are potential reservoirs of resistance determinants that can be mobilized into pathogens over a period of time. Elucidating the resistance mechanisms in such bacteria could help future antibiotic discoveries. This research is a preliminary study conducted to determine the effects of ciprofloxacin (CIP) on the intrinsically resistant Gram-positive soil bacterium Streptomyces coelicolor. The effect was investigated by performing 2-DE on total protein extracts of cells exposed to sub-lethal concentrations of ciprofloxacin as compared to the controls. Protein identification by MALDI-TOF/TOF revealed 24 unique differentially expressed proteins, which were statistically significant. The down-regulation of proteins involved in carbohydrate metabolism indicated a shift in the cell physiology towards a state of metabolic shutdown. Furthermore, the observed decline in protein levels involved in transcription and translation machinery, along with depletion of enzymes involved in amino acid biosynthesis and protein folding could be a cellular response to DNA damage caused by CIP, thereby minimizing the effect of defective and energetically wasteful metabolic processes. This could be crucial for the initial survival of the cells before gene level changes could come into play to ensure survival under prolonged adverse conditions. These results are a first attempt towards profiling the proteome of S. coelicolor in response to antibiotic stress. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. Soil-dwelling bacteria could serve as a reservoir of resistance determinants for clinically important bacteria. In this work, we investigated, for the first time, the differential proteomic profile of S. coelicolor cells in response to sub-inhibitory concentrations of Ciprofloxacin using 2-DE. Results indicate a shift in the cell physiology towards a state of metabolic shutdown, possibly to counter the DNA damage by ciprofloxacin. Further, up-regulation of GAPDH, RNA pol mRNA and Translation IF2 protein indicates a reprogramming of the cell for long-term survival. This study could serve as a basis for further investigations to elucidate the general mechanism by which soil bacteria exhibit resistance to fluroquinolones. This may help in developing new drug protocols and inventing novel drugs to counter resistance to this class of antibiotics in pathogenic bacteria.

Transcriptomic and morphological profiling of Aspergillus fumigatus Af293 in response to antifungal activity produced by Lactobacillus plantarum 16

The morphological effects of an antifungal activity produced by Lactobacillus plantarum 16, a malt-production steep water isolate, on two food-associated fungi were examined microscopically. Spore germination was completely inhibited in Aspergillus fumigatus and Rhizopus stolonifer upon treatment with concentrated cell-free supernatant (cCFS) of strain 16. Furthermore, addition of antifungal cCFS to germ tubes and hyphae halted further development compared to untreated controls. Transcriptome analysis of A. fumigatus Af293 following exposure to antifungal cCFS revealed a number of genes with altered transcription involved in a variety of cellular functions, most notably cell metabolism, suggesting a global metabolic shutdown and subsequent cell death. Increased transcription of the global regulator LaeA was also observed indicating that exposure to the antifungal activity caused a cellular stress response.

Protection against Myocardial Ischemia-Reperfusion Injury at Onset of Type 2 Diabetes in Zucker Diabetic Fatty Rats Is Associated with Altered Glucose Oxidation

BackgroundInhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury.MethodsIsolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements.ResultsT2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes.ConclusionsThe metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes.

Organ Failure in the ICU: Cellular Alterations

The physiological and biochemical abnormalities that constitute multiple organ failure represent cellular perturbations that, importantly, need to be reconciled with a lack of significant cell death together with availability but impaired utilization of oxygen. In conjunction with the relatively rapid ability of the organ to recover in surviving patients, a paradigm of metabolic shutdown triggered by a decrease in mitochondrial energy production appears increasingly valid. This review discusses data demonstrating temporal changes in oxygen utilization through the septic process, evidence for mitochondrial derangements, and recovery of mitochondrial function preceding clinical recovery.

Aluminum phosphide poisoning: an unsolved riddle

Aluminum phosphide (ALP), a widely used insecticide and rodenticide, is also infamous for the mortality and morbidity it causes in ALP-poisoned individuals. The toxicity of metal phosphides is due to phosphine liberated when ingested phosphides come into contact with gut fluids. ALP poisoning is lethal, having a mortality rate in excess of 70%. Circulatory failure and severe hypotension are common features of ALP poisoning and frequent cause of death. Severe poisoning also has the potential to induce multi-organ failure. The exact site or mechanism of its action has not been proved in humans. Rather than targeting a single organ to cause gross damage, ALP seems to work at the cellular level, resulting in widespread damage leading to multiorgan dysfunction (MOD) and death. There has been proof in vitro that phosphine inhibits cytochrome c oxidase. However, it is unlikely that this interaction is the primary cause of its toxicity. Mitochondria could be the possible site of maximum damage in ALP poisoning, resulting in low ATP production followed by metabolic shutdown and MOD; also, owing to impairment in electron flow, there could be free radical generation and damage, again producing MOD. Evidence of reactive oxygen species-induced toxicity owing to ALP has been observed in insects and rats. A similar mechanism could also play a role in humans and contribute to the missing link in the pathogenesis of ALP toxicity. There is no specific antidote for ALP poisoning and supportive measures are all that are currently available.

Site-Mapping of In Vitro S-nitrosation in Cardiac Mitochondria: Implications for Cardioprotection

S-nitrosation (SNO) of mitochondrial protein cysteines can be cardioprotective. Several targets have been implicated, yet the scope and identification of specific residues has not been fully assessed. To address this, a comprehensive assessment of mitochondrial SNO-modifiable cysteines was performed to determine nitric oxide (NO) susceptible pathways and identify novel mechanisms of oxidative cardioprotection. The biotin switch assay and mass spectrometry were used on rat cardiac mitochondrial lysates treated with the nitric oxide donor, S-nitrosoglutathione, and controls (n=3) to map 83 SNO-modified cysteine residues on 60 proteins. Of these, three sites have been reported, 30 sites are new to 21 proteins previously known to be S-nitrosated but which lacked site-specific information and 50 sites were found on 39 proteins not previously implicated in SNO pathways. The SNO-modifications occurred in only a subset of available cysteines, indicating a specific targeted effect. Functional annotation and site-specificity analysis revealed a twofold greater nitric oxide-susceptibility for proteins involved in transport; including regulators of mitochondrial permeability transition suggesting SNO-regulation and a possible protective mechanism. Additionally, we identified many novel SNO-modified proteins with cardioprotective potential involved in the electron transport chain, tricarboxylic acid cycle, oxidative stress defense, fatty acid and amino acid metabolism. These findings suggest that SNO-modification may represent a novel mechanism for the regulation of oxidative phosphorylation and/or cell death. S-nitrosation of mitochondrial permeability transition-associated proteins represents an intriguing potential link to cardioprotection.

Metabolic shutdown in Escherichia coli cells lacking the outer membrane channel TolC

The outer membrane channel TolC is a key component of multidrug efflux and type I secretion transporters in Escherichia coli. Mutational inactivation of TolC renders cells highly susceptible to antibiotics and leads to defects in secretion of protein toxins. Despite impairment of various transport functions, no growth defects were reported in cells lacking TolC. Unexpectedly, we found that the loss of TolC notably impairs cell division and growth in minimal glucose medium. The TolC-dependent phenotype was further exacerbated by the loss of ygiB and ygiC genes expressed in the same operon as tolC and their homologues yjfM and yjfC located elsewhere on the chromosome. Our results show that this growth deficiency is caused by depletion of the critical metabolite NAD(+) and high NADH/NAD(+) ratios. The increased amounts of PspA and decreased rates of NADH oxidation in Delta tolC membranes indicated stress on the membrane and dissipation of a proton motive force. We conclude that inactivation of TolC triggers metabolic shutdown in E. coli cells grown in minimal glucose medium. The Delta tolC phenotype is partially rescued by YgiBC and YjfMC, which have parallel functions independent from TolC.

Highlights of This Issue

Chemotherapy is used to treat metastatic/recurrent nasopharyngeal carcinoma (NPC), but there is a need for reliable biomarkers to predict treatment outcome early. Wang and colleagues explored the role of Epstein-Barr virus (EBV) clearance rate by quantifying serial changes of circulating EBV DNA concentration in NPC patients undergoing chemotherapy. They found that the rate of EBV clearance within the first month of treatment reflects chemosensitivity and predicts tumor response and patient survival. These results suggest that clearance of EBV DNA could be used as an early tumor response marker, and NPC patients with a slow plasma EBV DNA clearance rate may be considered for a chemotherapy regimen change.Cancer stem cell (CSC)–targeted therapeutic interventions, such as immunotherapy, hold promise for treatment of human cancers. Di Tomaso and colleagues performed an immunobiological characterization of a large panel of glioblastoma multiforme (GBM) CSC lines and paired non-CSC lines cultured in FBS. They found that T-cell responses against CSCs pretreated with IFN-γ could be induced in vitro. Notably, CSCs, but not autologous FBS-cultured cells, could inhibit allogeneic T-cell proliferation. These results could help to identify GBM patients with CSCs that can be targeted by immunotherapy.Mechanism-driven drug discovery relies on a thorough validation of molecular targets whose inhibition selectively kills cancer cells with a minimal effect on normal cells. In this study, Jia and colleagues identified and validated the SCF E3 ubiquitin ligase component SAG as a novel anticancer and radiosensitizing target. They found that SAG is overexpressed in a number of human primary cancers, and that silencing SAG with siRNA selectively kills cancer cells and sensitizes radioresistant cancer cells. Thus, development of small molecule inhibitors or RNAi-based therapy targeting SAG is a promising cancer treatment strategy.GMX1777 is a novel inhibitor of nicotinamide phosphoribosyl-transferase, an enzyme involved in NAD biosynthesis. Kato and colleagues used in vitro and in vivo models of head and neck cancer (HNC) to show that GMX1777 can enhance radiation efficacy via interference with DNA repair and tumor angiogenesis. Further, FDG-PET imaging corroborated the metabolic shutdown in these tumors. This study illustrates a potential therapeutic opportunity in targeting tumor metabolism, and suggests that GMX1777 plus radiotherapy warrants further clinical evaluation in patients with HNC.

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Is MOF an outcome parameter or a transient, adaptive state in critical illness?

The term 'multiorgan failure' (MOF) carries the negative connotation of major homeostatic breakdown and severe malfunction. However, this traditional paradigm may not be necessarily accurate. This review will investigate the rationale for no longer considering MOF to be simply a 'failed' pathophysiological state. Multiorgan failure is characterized by a hypometabolic, immunodepressed state with clinical and biochemical evidence of decreased functioning of the body's organ systems. Notwithstanding these findings, evidence for cell death is scarce and organ recovery is frequently the rule in surviving patients without pre-existing organ disease. Decreased mitochondrial activity appears to play a key role in the processes underlying MOF, both as a victim and a player. Reduced ATP production will compromise normal metabolic functioning. To protect itself from dying, the cell may adapt by decreasing its metabolic rate, and this is clinically manifest as organ dysfunction. Mitochondrial modulation may thus represent an important therapeutic target. The concept of MOF could be revisited as a transient state of metabolic shutdown analogous to hibernation. Avoiding the detrimental effects of inappropriate and counter-adaptive iatrogenic interventions is an important cornerstone of therapeutic management.

Mitochondrial function in sepsis: Acute phase versus multiple organ failure

To describe temporal changes in mitochondrial function during the septic process, including the recovery phase. Literature review. Clinical studies and laboratory models. Biochemical and ultrastructural mitochondrial abnormalities have been recognized in in vivo, ex vivo, and in vitro laboratory models of sepsis for >30 yrs. Short-term models show variable effects on mitochondrial function and structure; this is likely related to differences in model design, including species, organs studied, degree of septic insult, and degree of resuscitation. Longer-term models more consistently reveal mitochondrial dysfunction and damage. There is a rebound increase in oxygen consumption and resting energy expenditure in the recovery phase of sepsis. This could reflect mitochondrial recovery (biogenesis) that may restore the energy supply needed to fuel restorative metabolic processes and enable patient survival. Mitochondrial dysfunction seems to be intrinsically involved in the pathogenesis of multiple organ failure. As a consequence of a progressive decrease in energy availability, metabolism must decrease or the cell will die. The interplay between adenosine 5'-triphosphate supply and demand, dictated by the degree of mitochondrial dysfunction and the level of metabolic shutdown (analogous to a hibernation-type response), seems to be crucial in determining outcome. Further studies are needed to confirm this hypothesis.