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 exposed to H(2) 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.