Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

Enhancement of mitochondrial physiological function prevents sepsis-induced dysfunction. The present study aimed to elucidate the mechanism by which hydrogen (H₂) affects mitochondrial function in a wild-type (WT) and homozygous nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (KO, Nrf2^-/-) murine model of sepsis. In myocardial tissues with severe sepsis, H₂ gas treatment reduced mitochondrial dysfunction, whereas zinc protoporphyrin (ZnPPIX) negated these beneficial effects. H₂ treatment upregulated the protein expression of mitofusin-2 (Mfn2), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and protein heme oxygenase-1 (HO-1) in WT mice with severe sepsis but not in their Nrf2^-/- counterparts, and this upregulation was inhibited in the presence of ZnPPIX. In conclusion, the mechanism by which H₂ limits organ damage in mice with severe sepsis involves HO-1, whereas the mechanism that limits severe sepsis-related mitochondrial dysfunction involves both HO-1 and Nrf2.