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

Table 1 Reducing (antioxidant) agents in sepsis

Molecule (redox potential)	Water solubility	Lipid solubility	Mitochondrial entry	Direct H2O2 reactivity	Effective in sepsis
N-acetylcysteine (-240 millivolts)	High	Low	Indirect (boosts glutathione synthesis)	Low	No. Reacts weakly with H2O2; indirect via glutathione synthesis
Selenium (selenite) (+740 millivolts)	High	Low	Incorporated into selenoproteins inside mitochondria	Very low	No. Does not react directly with H2O2; glutathione peroxidase dependent
Vitamin C (+80 millivolts)	High	Very low	Via SVCT2/GLUT transporters	Moderate	No. Reduce H2O2 directly, less efficient than thiol compounds
Vitamin E (+500 millivolts)	Very low	High	Embeds in cell membranes	Very low	Inconclusive; insufficient data
Coenzyme Q (+55 millivolts)	Very low	High	Synthesized in mitochondria	Very low	Inconclusive; insufficient data
Melatonin (+650 millivolts)	Low	High (amphiphilic)	Direct diffusion; high accumulation	High	Yes. Directly scavenge H2O2
Dihydrolipoic acid (-320 millivolts)	Moderate	Moderate (amphiphilic)	Direct diffusion; high accumulation	High	Unknown. Strong thiol antioxidant; directly reduces H2O2; regenerates vitamin C, E, and glutathione
Sodium thiosulfate (+169 millivolts)	High	Very low	No direct entry; indirect protection	Very high	Unknown. Strong H2O2 scavenger in extracellular-intravascular space

The distinctions between melatonin and the first five antioxidants suggest that targeted reduction of hydrogen peroxide—particularly within mitochondria—constitutes a specific therapeutic strategy capable of resolving sepsis through restoration of mitochondrial redox homeostasis. The reducing (antioxidant) functions of melatonin can be distributed among sodium thiosulfate, a water soluble, direct chemical, extracellular reducing agent, and R-dihydrolipoic acid, a lipid soluble, intracellular, direct chemical and biological, reducing agent capable of enhancing cellular antioxidant (reductive) capacity. H₂O₂: Hydrogen peroxide.