Dissipation of the mitochondrial proton motive force drives sepsis pathogenesis and explains hyperlactatemia’s predictive value in sepsis mortality

Figure 4 Mitochondrial DNA oxidative damage: A diagrammatic representation illustrating the mutagenic impact of electron transport chain-derived hydrogen peroxide on mitochondrial DNA. Mitochondrial DNA (mtDNA) is highly susceptible to oxidative damage. Exposure to hydrogen peroxide (H₂O₂) during sepsis leads to mtDNA oxidative damage. This damage gives rise to mtDNA mutations (mitochondrial heteroplasmy), resulting in transcriptional miscoding of electron transport chain (ETC) complexes and the subsequent synthesis of defective and mutated ETC protein subunits. These dysfunctional proteins disrupt electron flow, causing an elevated rate of electron leakage. The prematurely ‘leaked’ electrons interact with nearby molecular oxygen within the mitochondrial matrix, generating superoxide, which is subsequently converted to H₂O₂ through the action of superoxide dismutase. The H₂O₂ leads to additional mtDNA damage resulting in an iterative cycle of oxidative mtDNA damage, defective ETC protein complexes and progressively greater levels of H₂O₂. This disruption initiates a self-amplifying (vicious) cycle of increasing H₂O₂ production and ETC dysfunction while compromising oxidative phosphorylation and ATP synthesis. The elevated H₂O₂ levels inhibit the mitochondrial energy flux and dissipate the proton motive force while simultaneously contributing to immunosuppression through H₂O₂-induced systemic lymphocyte apoptosis. This process may play a critical role in the development of post-sepsis syndrome. PMF: Proton motive force; mtDNA: Mitochondrial DNA; ETC: Electron transport chain; H₂O₂: Hydrogen peroxide.