New Breakthrough Study Identifies First Molecular Target of Hydrogen in Human Cells

A groundbreaking paper published this week in Redox Biology reveals the first clearly defined molecular target of molecular hydrogen (H₂), reshaping scientific understanding of how hydrogen exerts its therapeutic effects. The study, co-authored by Dr. Tyler W. LeBaron of the Molecular Hydrogen Institute (MHI), identifies the Rieske iron-sulfur protein (RISP), a critical component of mitochondrial Complex III, as a primary target of H₂.

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This discovery marks one of the most significant mechanistic breakthroughs in hydrogen research since the 2007 Nature Medicine publication that catalyzed modern interest in H₂.

Key Findings

The research demonstrates that:

• Hydrogen specifically targets the iron-sulfur protein (RISP) in a manner that promotes its LONP1-mediated degradation within the mitochondrial electron transport chain.

• This interaction temporarily suppresses Complex III activity, signaling the cell that a stressor is present.

• The cell responds by activating the mitochondrial unfolded protein response (UPRmt) — a protective, hormetic pathway that enhances cellular resilience.

• Within hours, the cell rebuilds and upregulates RISP, restoring and improving mitochondrial function.

The study provides a unified explanation for many previously “paradoxical” observations in hydrogen research, such as both decreases and increases in oxidative markers, changes in mitochondrial potential, and sustained protective effects even after H₂ levels return to baseline.

A Paradigm Shift

“These findings show that hydrogen is not a biologically inert byproduct of a healthy microbiome, as long believed,” said Dr. LeBaron. “It acts as a mitochondrial signaling molecule, similar to nitric oxide or hydrogen sulfide, but with its own unique evolutionary and biochemical profile.”

The researchers suggest that the iron-sulfur cluster in RISP may have ancient evolutionary roots, linking hydrogen’s effects to primordial mitochondrial systems once dependent on hydrogenases.

Implications for Exercise, Medicine and Research

This discovery:

• Moves hydrogen therapy beyond the “antioxidant hypothesis”

• Establishes a precise, testable mechanism for future clinical trials

• Explains hydrogen’s pleiotropic effects across hundreds of disease models

• Opens new avenues for mitochondrial medicine, exercise physiology, and redox biology

Identifying a primary molecular target allows researchers to build more rigorous studies, refine dosing strategies, and deepen clinical relevance,” said May Anderson, MHI Research Director. “This is the mechanistic clarity the field has been waiting for.”