Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain.

Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, nonketotic hyperglycinemia, with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency but the consequences for energy mechanisms remain unknown. We find that brains of young-attenuated mutant mice show a 1.5-fold increase in glycine and no change in folate responsiveness. They are, however, reduced > 5-fold in GLDC, indicate decrease in the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase complex as well as rise in signatures of astrocyte mitochondrial β-oxidation of fatty acids proportionate to mutation severity and activation of pyruvate dehydrogenase. Together these data reveal a novel GLDC mechanism that regulates catabolic mitochondrial energy processes in both attenuated and severe brain disease and suggest new targets in energy metabolism to treat nonketotic hyperglycinemia.