Glycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth

The folic acid cycle mediates the transfer of one-carbon (1C) units to support nucleotide biosynthesis. While the importance of serine as a mitochondrial and cytosolic donor of folate-mediated 1C units in cancer cells has been thoroughly investigated, a potential role of glycine oxidation remains unclear. We developed an approach for quantifying mitochondrial glycine cleavage system (GCS) flux by combining stable and radioactive isotope tracing with computational flux decomposition. We find high GCS flux in hepatocellular carcinoma (HCC), supporting nucleotide biosynthesis. Surprisingly, other than supplying 1C units, we found that GCS is important for maintaining protein lipoylation and mitochondrial activity. Genetic silencing of glycine decarboxylase inhibits the lipoylation and activity of pyruvate dehydrogenase and impairs tumor growth, suggesting a novel drug target for HCC. Considering the physiological role of liver glycine cleavage, our results support the notion that tissue of origin plays an important role in tumor-specific metabolic rewiring. [Display omitted] •Glycine cleavage system (GCS) is highly expressed in hepatocellular carcinoma (HCC)•Mitochondrial glycine-derived 1C units support nucleotide biosynthesis in the cytosol•GLDC activity is important for mitochondrial protein lipoylation in HCC•Silencing glycine decarboxylase impairs mitochondrial activity and HCC tumor growth Mukha, Fokra, and colleagues show high expression of glycine cleavage system genes in hepatocellular carcinoma associated with high glycine cleavage flux. Surprisingly, other than supplying one-carbon units for biosynthesis, glycine oxidation is found to facilitate mitochondrial protein lipoylation. Genetic silencing of glycine decarboxylase impairs lipoylated enzyme activity and mitochondrial function.