Mitochondrial one-carbon metabolism

The term "mitochondrial one-carbon metabolism" refers to a critical set of interconnected metabolic pathways located within mitochondria, not a single molecule or protein, but rather an ensemble function performed by specific enzymes, cofactors, and transporters. Mitochondrial one-carbon metabolism is a compartmentalized metabolic network centered around the mitochondrial folate pathway and associated enzymes (notably SHMT2, MTHFD2, and ALDH1L2), which convert serine and glycine into one-carbon donors, NAD(P)H, and other biosynthetic precursors. This pathway provides essential one-carbon units (in the form of formate) for nucleotide synthesis, methylation processes, redox homeostasis, and the maintenance of cellular energy and biosynthetic needs. It is especially crucial in cancer, where increased demand for nucleotides and methylation heightens pathway activity, rendering mitochondrial one-carbon enzymes attractive therapeutic targets. However, the pathway is not a discrete macromolecular entity (i.e., not a classical receptor, enzyme, or transporter), and "mitochondrial one-carbon metabolism" should be more precisely represented by its constituent enzymes for drug targeting purposes.

Other names

Mitochondrial 1C metabolismMitochondrial folate cycleMitochondrial serine/glycine pathway

Inhibition of one-carbon pathway enzymes limits nucleotide synthesis and methyl group availability, suppressing cancer cell proliferation and inducing cell death