Mitochondrial Dysfunction and Antioxidant Therapy in Sepsis

Rocha, Milagros; Herance, José Raúl; Rovira, S.; Hernández‐Mijares, Antonio; Víctor, Víctor M.

doi:10.2174/187152612800100189

Cited by 81 publications

(72 citation statements)

References 161 publications

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“…W-peptide (chemoattractant) was Of note, the extent of mitochondrial dysfunction in the lungs has been shown to correlate with mortality in sepsis (19,20). Approaches to prevent mitochondrial dysfunction or to restore mitochondrial bioenergetics may diminish the severity of sepsis-associated lung injury (21)(22)(23).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

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Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.

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Section: Reagents and Antibodiesmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

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“…ROS cause tissue damage and they can also trigger apoptosis. Therefore, antioxidants and radical scavengers have been proposed as a possible therapy and have shown some efficacy in sepsis models [71, 93–95]. More recently, ROS scavengers especially targeted to the mitochondria, such as MitoQ, SkQ1, MitoE, and Tempol conjugates, which accumulate in the mitochondria manifold raising their effective concentration at the sub-cellular sites needed, were proposed as a novel strategy (reviewed in [96]).…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

Lee

Hüttemann

2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

130

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Mitochondrial dysfunction is increasingly recognized as an accomplice in most of the common human diseases including cancer, neurodegeneration, diabetes, ischemia/reperfusion injury as seen in myocardial infarction and stroke, and sepsis. Inflammatory conditions, both acute and chronic, have recently been shown to affect mitochondrial function. We here discuss the role of oxidative phosphorylation (OxPhos), focusing on acute inflammatory conditions, in particular sepsis and experimental sepsis models. We discuss mitochondrial alterations, specifically suppression of oxidative metabolism and the role of mitochondrial reactive oxygen species in disease pathology. Several signaling pathways including metabolic, proliferative, and cytokine signaling affect mitochondrial function and appear to be important in inflammatory disease conditions. Cytochrome c oxidase (COX) and cytochrome c, the latter of which plays a central role in apoptosis in addition to mitochondrial respiration, serve as examples for the entire OxPhos system since they have been studied in more detail with respect to cell signaling. We propose a model in which inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, including Tyr304 phosphorylation of COX catalytic subunit I. This results in inhibition of OxPhos, a reduction of the mitochondrial membrane potential, and consequently a lack of energy, which can cause organ failure and death as seen in septic patients.

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“…There is a hyperoxidative state in sepsis [1-5], which results from an imbalance between Doxidants and antioxidants, and includes oxidative modification of cellular macromolecules, induction of cell death by apoptosis and structural tissue damage. Malondialdehyde (MDA) is an end-product formed during oxidative stress, concretely lipid peroxidation [4,5].…”

Section: Introductionmentioning

confidence: 99%

Sustained high serum malondialdehyde levels are associated with severity and mortality in septic patients

et al. 2013

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IntroductionThere is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week.MethodsWe performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six -month mortality. The association between continuous variables was carried out using Spearman’s rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables.ResultsWe found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was lower in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure.ConclusionsTo our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.

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Mitochondrial Dysfunction and Antioxidant Therapy in Sepsis

Cited by 81 publications

References 161 publications

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

Sustained high serum malondialdehyde levels are associated with severity and mortality in septic patients

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