Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane

Mitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside mitochondria. Urea is required to convert ammonia protect brain from toxicity. tightly channeled out mitochondria, indicating activity these relies upon their coordinated interaction with each other, perhaps a cluster. This view supported by mutations surface residues proteins impair ureagenesis patients, but do not affect protein stability or catalytic activity. We find NAGS, CPS1, OTC liver mitochondria can associate inner mitochondrial membrane (IMM) be co-immunoprecipitated. Our in-silico analysis vertebrate NAGS proteins, least abundant enzymes, identified protein-protein region present only protein—“variable segment,” which mediates CPS1. Use super resolution microscopy showed CPS1 clusters hepatocyte These results indicate cluster, instead functioning either independently rigid multienzyme complex.