Abstract
<jats:p>Deuterium is a natural heavy isotope of hydrogen, containing a neutron as well as a proton, making it twice as heavy. Mitochondrial ATP synthase nanomotors are highly sensitive to deuterium, causing them to release reactive oxygen species (ROS) and reducing ATP synthesis. Metabolic processes have evolved to devise ways to reduce the deuterium load in the mitochondria, primarily, we argue, by exploiting several small hydrogen-containing molecular gases. When a gas is produced, deuterium, due to its extra weight, tends to stay behind in the aqueous phase, so the gas becomes deuterium-depleted (deupleted). Furthermore, many of the enzymes that synthesize these small gas molecules are designed to exclude deuterium by exploiting proton tunneling. The gut microbes play a crucial role in producing deupleted gas molecules, such as hydrogen gas (H2), methane (CH4), ammonia (NH3), and hydrogen sulfide (H2S). During inflammatory bowel disease (IBD), activated immune cells upregulate NADPH oxidase (NOX) to produce superoxide, which is converted to hydrogen peroxide (H2O2) by superoxide dismutase. Some microbes can convert H2O2 into two molecules of (likely deupleted) water through anaerobic respiration. H2O2 readily crosses the mitochondrial membrane, and human mitochondrial glutathione peroxidase can also convert H2O2 to water. The glutamate-glutamine exchange that takes place between astrocytes and neurons plausibly capitalizes on NH3 to safely deliver deupleted protons to neuronal mitochondria. In this paper, we investigate how small molecular hydrogen-containing gases are handled in metabolism, from a perspective that considers the roles that deuterium might play in metabolic policy.</jats:p>