Therapeutic Efficacy of Molecular Hydrogen: A New Mechanistic Insight

Abstract

Background: Molecular hydrogen (H2) is now recognized as a therapeutic gas for the treatment of numerous diseases including neurodegenerative diseases, metabolic disorders, and inflammatory diseases. Non- polar, neutral H2 is assumed to have health benefits facilitated by its passive diffusion across the human body immediately after administration and is considered a safe therapeutic inert gas that does not interfere with physiological enzymatic reactions. The effects of H2 on mammalian cells are assumed to be based on non-enzymatic reactions with reactive oxygen species (ROS) exhibiting extremely high reactivity. However, many reports on therapeutic applications of H2 have the limitation to regard H2 only as a scavenger for the hydroxyl radical and peroxynitrite. Methods: Apart from this proposed principle, a new possible mechanism of H2 activation and consumption in mammalian cells is considered in this review, which is specifically focused on the mitochondrial complex I that has a close evolutionary relationship with energy-converting, membrane-bound [NiFe]-hydrogenases (MBH). Notably, the possibility that H2 may function as both electron and proton donor in the ubiquinone-binding chamber of complex I is discussed. Results: H2 is proposed to act as the rectifier of the mitochondrial electron flow in the disordered or pathological state when the accumulation of electrons leads to ROS production, specifically during the re-supply of O2 after hypoxia in the mitochondria. Conclusion: Furthermore, H2 is proposed to convert the quinone intermediates to the fully reduced ubiquinol, thereby increasing the antioxidant capacity of the quinone pool as well as preventing the generation of ROS.

Study details

Article type

Review

Disease / injury model

Neurodegenerative diseases, metabolic disorders, inflammatory diseases (general discussion)

Dose comparison

The article references studies with different H2 concentrations (e.g., 0.8 mM in water, 2% and 3% H2 gas) and discusses their effective blood levels (5–20 μM) and therapeutic outcomes.

Dose-dependent effect

Yes

Outcome

Positive

Findings

The article proposes a new mechanistic insight into the therapeutic efficacy of molecular hydrogen (H2), suggesting that H2 acts not only as a scavenger of reactive oxygen species but also as a rectifier of mitochondrial electron flow by donating electrons and protons to ubiquinone intermediates in complex I, thereby preventing ROS generation and increasing antioxidant capacity.