The Rieske iron-sulfur protein is a primary target of molecular hydrogen

The mechanisms underlying the biomedical effects of molecular hydrogen (H₂) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H₂ is biologically inert. We demonstrate that H₂ is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H₂ induces the mitochondrial unfolded protein response (UPR^mt) in cultured cells exposed to H₂ and in mouse liver after H₂ water administration. H₂ suppressed electron transport chain complex III activity in mouse liver homogenates to 78.5 % within 2 min. Given the evolutionary link with hydrogenases, we examined RISP as a potential target of H₂. We found that H₂ promotes RISP degradation within 1 h in cultured cells by activating mitochondrial Lon peptidase 1 (LONP1). Loss of RISP and subsequent UPR^mt induction may explain the pleiotropic and paradoxical effects of H₂. These findings identify RISP as a primary target of H₂, demonstrating that H₂ is biologically active as a signaling molecule.