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 H-2 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 mitochondria' complex I that has a close evolutionary relationship with energy-converting, membrane-bound [NiFe]-hydrogenases (MBH). Notably, the possibility that H-2 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 mitochondria' 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.