Do Methylation Pathways Carry Microbially Derived Deuterium-Depleted Methyl Groups to Support Mitochondrial Health?

Many chronic diseases are associated with mitochondrial dysfunction, and many of these same diseases are also associated with gut dysbiosis. In this paper, we link these two factors together by arguing that gut dysbiosis leads to mitochondrial dysfunction through an excess supply of deuterium to the mitochondrial ATPase pumps. We further argue that impaired one-carbon metabolism plays a central role in the disease process. One-carbon metabolism (also known as the methylation pathway) is a fundamental biochemical process involving the transfer of methyl groups from one molecule to another, to carry out many cellular functions, including DNA, RNA, and protein methylation and phosphatidylcholine synthesis. The pathway centers on S-adenosylmethionine (SAMe), the universal methyl donor. The methyl group is sourced from methyl-tetrahydrofolate, while methionine, glycine, serine, and formaldehyde are carriers of one-carbon units. An overlooked aspect is the crucial role that the gut microbiome plays in assuring that the one-carbon units are virtually free of deuterium. Deuterium is a natural heavy isotope of hydrogen, and it damages the ATPase pumps in the mitochondria. Microbes produce extremely deuterium depleted (deupleted) hydrogen gas which they use as a reducing agent to convert carbon dioxide into organic molecules, such as acetate, butyrate and formate. We show here through an in-depth review of methylation and demethylation processes how they are used to deliver deupleted protons to the mitochondria, to protect them from damage. Toxic exposures to organophosphate insecticides and deficiencies in nutrients such as methionine, choline, betaine, and serine can impair methylation pathways, causing disease through co-causality of mitochondrial dysfunction. We further suggest that synthetic versions of critical nutrients such as choline and methionine may be problematic because they supply methyl groups that are not deuterium depleted.