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

Abstract

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 (UPRmt) 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 UPRmt 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.

Study details

Article type

Original Research

Disease / injury model

None (focus is on mechanism in healthy cells and animals)

Duration

4 weeks

Dose comparison

The study examines different concentrations and durations of H2 exposure (2.5–3.5 mM in water, 10% H2 gas) and their effects on mitochondrial function and protein levels.

Dose-dependent effect

Yes

Outcome

Mixed

Findings

Molecular hydrogen (H2) is biologically active and specifically targets the Rieske iron-sulfur protein (RISP) in mitochondrial complex III, leading to its degradation via LONP1, suppression of complex III activity, induction of the mitochondrial unfolded protein response (UPRmt), and subsequent adaptive mitochondrial changes.