Do small hydrogen-containing gas molecules support low deuterium in mitochondrial water?

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, because it impedes the flow of protons through the nanomotors and causes the γ C-terminal helix to unwind. It appears that 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. We propose that, when a gas is produced, deuterium, due to its extra weight, tends to stay behind in the aqueous medium, so the gas becomes deuterium-depleted. Furthermore, many of the enzymes that synthesize and/or metabolize these small gas molecules fractionate out deuterium by exploiting proton tunneling. We hypothesize that the gut microbes play a crucial role in producing deuterium-depleted gas molecules, such as hydrogen gas (H 2 ), methane (CH 4 ), ammonia (NH 3 ), hydrogen sulfide (H 2 S), trimethylamine (TMA), formaldehyde (HCHO), and methanethiol (CH 3 SH). Gut microbial metabolism of TMA likely provides a low-deuterium source of one-carbon (1C) units to fuel the methylation pathway in the host. The glutamate-glutamine exchange that takes place between astrocytes and neurons plausibly capitalizes on NH 3 to preferentially deliver 1 H (protons) to neuronal mitochondria. Red blood cells actively import NH 3 while the cation NH 4 + is excreted in the urine, possibly as a strategy to fractionate out deuterium. In this paper, we investigate how small molecular hydrogen-containing gases are handled in metabolism, from a perspective that considers that these gases may serve a useful role in reducing the deuterium content in the mitochondria. Our hypothesis awaits validation by expert researchers who can perform appropriate experiments to test the hypothesis.