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. Nonpolar,
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
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.