Sepsis: Evidence-based pathogenesis and treatment

Figure 1 Krebs cycle derived reducing equivalents (NADH, FADH2) donate electrons that are processed by the electron transport chain during oxidative phosphorylation. Up to 5% of electrons (e^-) will normally escape the electron transport chain (ETC) into the mitochondrial matrix (electron leakage)[14-16]. These electrons combine with molecular oxygen (O₂) to form superoxide anion radical (O₂^-), which is metabolized by superoxide dismutase (SOD) to hydrogen peroxide (H₂O₂) that in turn is converted to glutathione disulfide (GS-SG) and water via glutathione peroxidase (GPX) and its reducing co-factor glutathione (GSH). Critical illness hypermetabolic states increase ETC activity leading to enhanced electron leakage and far greater H₂O₂ formation, which can deplete cellular GSH resulting in a build-up of H₂O₂ in cells and blood causing bioenergetic dysfunction and organ failure.