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

Abstract

Sepsis remains a major cause of global mortality, yet its underlying pathogenesis is still incompletely understood. The current Sepsis-3 definition describes sepsis as a “life-threatening organ dysfunction caused by a dysregulated host response to infection”, but offers no mechanistic explanation for how infection or inflammation lead to metabolic collapse and organ failure. This work proposes a unifying biochemical model in which sepsis originates as an intramitochondrial disturbance of redox homeostasis triggered by an early hypermetabolic surge in mitochondrial hydrogen peroxide. According to this framework, excess hydrogen peroxide overwhelms mitochondrial reductive buffering systems, leading to aconitase (Krebs cycle) inhibition, impaired NADH and FADH₂ generation, dissipation of the proton motive force, and subsequent failure of oxidative phosphorylation. This sequence provides a coherent explanation for hallmark features of sepsis, including hyperlactatemia, metabolic acidosis, hypothermia, ATP depletion, bioenergetic failure and increased mortality. The model also accounts for interindividual variability in sepsis susceptibility through differences in mitochondrial reductive capacity and offers insight into why animal models fail to translate to humans. Additionally, toxic systemic hydrogen peroxide elevation may contribute independently to sepsis heterogeneity by oxidatively inhibiting multiple enzyme systems and inducing lymphocyte apoptosis, providing a mechanistic basis for immunosuppression and post-sepsis syndrome. Confirming a role for hydrogen peroxide in initiating and perpetuating these events positions impaired mitochondrial redox homeostasis as a central driver of sepsis pathogenesis and generates testable predictions regarding specific therapy and future research.

Keywords: Sepsis; Hydrogen peroxide; Proton motive force; Sodium thiosulfate; Dihydrolipoic acid

Core Tip: Despite extensive research spanning several decades and numerous unsuccessful clinical trials, the underlying cause of sepsis remains elusive. However, the characteristic metabolic disturbances observed in sepsis—such as hyperlactatemia, bioenergetic failure, metabolic acidosis, hypothermia, and oxidative stress—can be explained by dissipation of the mitochondrial proton motive force. Emerging evidence suggests that hydrogen peroxide–mediated disruption of this proton gradient represents the proximal mechanism driving the pathogenesis of sepsis.