# Revisiting molecular hydrogen signaling in mitochondria: Is the Rieske protein the entry point or a downstream sentinel?
> ミトコンドリアにおける水素シグナル伝達の再考：RieskeタンパクはH2作用の入口か下流センチネルか


## Abstract

This review examines recent evidence that molecular hydrogen (H2) suppresses mitochondrial Complex III activity through the Rieske iron-sulfur protein (RISP) and subsequent LONP1-mediated proteolysis, prompting a reassessment of whether RISP constitutes the primary molecular entry point for H2 signaling. From evolutionary and structural perspectives, RISP belongs to a broader family of hydrogenase-like mitochondrial redox proteins sharing ancient iron-sulfur architectures. Candidate proteins including succinate dehydrogenase subunit B (SDHB), Complex I iron-sulfur subunits, and CISD-family [2Fe-2S] proteins exhibit comparable redox properties and strategic positions within mitochondrial bioenergetic networks. The review organizes these candidates into a hierarchical, testable framework and proposes comparative structural, biochemical, and proteostatic approaches to identify the true molecular target of H2 in human mitochondria.

### Mechanism

H2 may suppress mitochondrial Complex III via the Rieske iron-sulfur protein (RISP), triggering LONP1-dependent proteolysis; however, SDHB, Complex I iron-sulfur subunits, and CISD-family [2Fe-2S] proteins are proposed as alternative primary molecular targets warranting comparative investigation.

## Bibliographic

- **Authors**: Ostojic SM
- **Journal**: Redox Biol
- **Year**: 2026
- **PMID**: [41496215](https://pubmed.ncbi.nlm.nih.gov/41496215/)
- **DOI**: [10.1016/j.redox.2026.104003](https://doi.org/10.1016/j.redox.2026.104003)
- **PMC**: [PMC12808497](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808497/)
- **Study type**: review
- **Delivery route**: not specified
- **Effect reported**: not assessed

## Delivery context

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

## Safety notes

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)

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> **Cite as**: H2 Papers — PMID 41496215. https://h2-papers.org/en/papers/41496215
> **Source**: PubMed PMID [41496215](https://pubmed.ncbi.nlm.nih.gov/41496215/)