Revisiting molecular hydrogen signaling in mitochondria: Is the Rieske protein the entry point or a downstream sentinel?

A recent study published in Redox Biology (Volume 88, December 2025, 103952) demonstrates that molecular hydrogen (H₂) rapidly suppresses mitochondrial Complex III activity through a mechanism involving the Rieske iron-sulfur protein (RISP) and subsequent LONP1-dependent proteolysis, challenging the long-standing view of H₂ as merely a selective radical scavenger. While these findings compellingly identify RISP as a key mediator of mitochondrial responses to H₂, its designation as the primary molecular target warrants broader consideration. From an evolutionary and structural standpoint, RISP belongs to a wider family of hydrogenase-like mitochondrial redox proteins that retain ancient iron-sulfur architectures. Proteins such as succinate dehydrogenase subunit B (SDHB), iron-sulfur subunits of Complex I, and CISD family [2Fe-2S] proteins share comparable redox logic and strategic positioning within mitochondrial bioenergetic networks. Here, these candidates are prioritized and placed into a hierarchical, testable framework, and specific comparative structural, biochemical, and proteostatic approaches are proposed to define the true molecular entry point of H₂ signaling in human mitochondria.