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

Frontiers in Physiology

Shivaprasad Bhuvanendran¹  Mendel Tuchman¹  Nantaporn Haskins¹  Nathaniel Stearrett²  Anna Gams³  Jyoti K. Jaiswal⁴  Ljubica Caldovic⁴  Hiroki Morizono⁴  Claudio Anselmi⁴  Kylie I. Krohmaly⁵  Erin Bonner⁵  Danielle Sohai⁵  Tomas Kanholm⁵  Kristen M. Kocher⁵  Jonathan LoTempio⁵ 

[1] Center for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United States;Computational Biology Institute, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States;Department of Biomedical Engineering, School of Engineering and Applied Sciences, The George Washington University, Washington, DC, United States;Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United States;School of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United States;

关键词: urea cycle;    N-acetylglutamate synthase;    carbamylphosphate synthetase 1;    ornithine transcarbamylase;    enzyme cluster;    mitochondria;   

DOI  :  10.3389/fphys.2020.542950

来源: DOAJ

【 摘 要 】

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

【 授权许可】

Unknown