Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity

Abstract

Serine hydroxymethyltransferase 2 (SHMT2) catalyzes the reversible conversion of 35 tetrahydrofolate (THF) and serine producing THF-conjugated one-carbon units and glycine in 36 the mitochondria. Biallelic SHMT2 variants were identified in humans and suggested to alter the 37 protein’s active site, potentially disrupting enzymatic function. SHMT2 expression has also been 38 shown to decrease with aging in human fibroblasts. Immortalized cells models of total SHMT2 39 loss or folate deficiency exhibit decreased oxidative capacity and impaired mitochondrial 40 complex I assembly and protein levels, suggesting folate-mediated one-carbon metabolism 41 (FOCM) and the oxidative phosphorylation system are functionally coordinated.