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

The mechanisms underlying the biomedical effects of molecular hydrogen (H 2 ) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H 2 is biologically inert. We demonstrate that H 2 is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H 2 induces the mitochondrial unfolded protein response (UPR mt ) in cultured cells and in mouse liver after H 2 water administration. H 2 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 H 2 . We found that H 2 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 H 2 . These findings identify RISP as a primary target of H 2 , demonstrating that H 2 is biologically active as a signaling molecule.