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 the mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2020.542950/full |
| _version_ | 1818561058298658816 |
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| author | Nantaporn Haskins Shivaprasad Bhuvanendran Claudio Anselmi Claudio Anselmi Anna Gams Tomas Kanholm Kristen M. Kocher Jonathan LoTempio Kylie I. Krohmaly Danielle Sohai Nathaniel Stearrett Nathaniel Stearrett Erin Bonner Mendel Tuchman Hiroki Morizono Hiroki Morizono Jyoti K. Jaiswal Jyoti K. Jaiswal Ljubica Caldovic Ljubica Caldovic |
| author_facet | Nantaporn Haskins Shivaprasad Bhuvanendran Claudio Anselmi Claudio Anselmi Anna Gams Tomas Kanholm Kristen M. Kocher Jonathan LoTempio Kylie I. Krohmaly Danielle Sohai Nathaniel Stearrett Nathaniel Stearrett Erin Bonner Mendel Tuchman Hiroki Morizono Hiroki Morizono Jyoti K. Jaiswal Jyoti K. Jaiswal Ljubica Caldovic Ljubica Caldovic |
| author_sort | Nantaporn Haskins |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T00:46:09Z |
| format | Article |
| id | doaj.art-d0513014ca26433bbf1cf3d4ad8f47b7 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-14T00:46:09Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-d0513014ca26433bbf1cf3d4ad8f47b72022-12-21T23:24:08ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-01-011110.3389/fphys.2020.542950542950Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial MembraneNantaporn Haskins0Shivaprasad Bhuvanendran1Claudio Anselmi2Claudio Anselmi3Anna Gams4Tomas Kanholm5Kristen M. Kocher6Jonathan LoTempio7Kylie I. Krohmaly8Danielle Sohai9Nathaniel Stearrett10Nathaniel Stearrett11Erin Bonner12Mendel Tuchman13Hiroki Morizono14Hiroki Morizono15Jyoti K. Jaiswal16Jyoti K. Jaiswal17Ljubica Caldovic18Ljubica Caldovic19Center for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesDepartment of Genomics and Precision Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United StatesDepartment of Biomedical Engineering, School of Engineering and Applied Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesComputational Biology Institute, Milken Institute School of Public Health, The George Washington University, Washington, DC, United StatesSchool of Medicine and Health Sciences, Institute for Biomedical Sciences, The George Washington University, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesDepartment of Genomics and Precision Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesDepartment of Genomics and Precision Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, United StatesDepartment of Genomics and Precision Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United StatesMitochondrial 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.https://www.frontiersin.org/articles/10.3389/fphys.2020.542950/fullurea cycleN-acetylglutamate synthasecarbamylphosphate synthetase 1ornithine transcarbamylaseenzyme clustermitochondria |
| spellingShingle | Nantaporn Haskins Shivaprasad Bhuvanendran Claudio Anselmi Claudio Anselmi Anna Gams Tomas Kanholm Kristen M. Kocher Jonathan LoTempio Kylie I. Krohmaly Danielle Sohai Nathaniel Stearrett Nathaniel Stearrett Erin Bonner Mendel Tuchman Hiroki Morizono Hiroki Morizono Jyoti K. Jaiswal Jyoti K. Jaiswal Ljubica Caldovic Ljubica Caldovic Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane Frontiers in Physiology urea cycle N-acetylglutamate synthase carbamylphosphate synthetase 1 ornithine transcarbamylase enzyme cluster mitochondria |
| title | Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane |
| title_full | Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane |
| title_fullStr | Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane |
| title_full_unstemmed | Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane |
| title_short | Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane |
| title_sort | mitochondrial enzymes of the urea cycle cluster at the inner mitochondrial membrane |
| topic | urea cycle N-acetylglutamate synthase carbamylphosphate synthetase 1 ornithine transcarbamylase enzyme cluster mitochondria |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2020.542950/full |
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