Molecular Hydrogen as a Dual Redox Modulator: Integration of Selective Neutralization and Mitochondrial Regulation via the Rieske Fe–S Protein

Molecular hydrogen (H₂) has traditionally been described as a selective antioxidant, primarily acting through the neutralization of highly reactive oxygen species such as the hydroxyl radical. However, recent advances suggest that this interpretation may be incomplete. Emerging evidence identifies the Rieske iron–sulfur protein (UQCRFS1) of mitochondrial complex III as a potential primary interaction site for H₂, pointing toward a more structured and regulatory mechanism. This work integrates recent findings on mitochondrial complex III assembly and regulation with newly proposed hydrogen–protein interactions, advancing a unified model in which H₂ acts as a modulator of electron transport chain dynamics. Specifically, we examine how the intrinsic sensitivity of the Rieske Fe–S protein to structural and processing variations may provide a mechanistic basis for hydrogen’s effects on reactive oxygen species (ROS) production and bioenergetic efficiency. Rather than acting as a simple radical scavenger, molecular hydrogen may operate as a regulator of mitochondrial redox homeostasis by interacting with a structurally and functionally critical node of the respiratory chain. This perspective supports a conceptual shift in which H₂ is considered a physiological modulator with potential systemic implications.