Therapeutic Efficacy of Molecular Hydrogen: A New Mechanistic Insight

BACKGROUND: Molecular hydrogen (H(2)) is now recognized as a therapeutic gas for the treatment of numerous diseases including neurodegenerative diseases, metabolic disorders, and inflammatory diseases. Non-polar, neutral H(2) 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 H(2) 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 H(2) 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 H(2) 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: H(2) 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 O(2) after hypoxia in the mitochondria. CONCLUSION: Furthermore, H(2) 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.