Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration
Photoreceptor cell death is the cause of vision loss in many forms of retinal disease. Metabolic dysfunction within the outer retina has been shown to be an underlying factor contributing to photoreceptor loss. Therefore, a comprehensive understanding of the metabolic pathways essential to photorece...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Ophthalmology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fopht.2023.1306019/full |
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| author | Shubha Subramanya Moloy T. Goswami Nicholas Miller Eric Weh Sraboni Chaudhury Li Zhang Anthony Andren Heather Hager Katherine M. Weh Costas A. Lyssiotis Costas A. Lyssiotis Costas A. Lyssiotis Cagri G. Besirli Thomas J. Wubben |
| author_facet | Shubha Subramanya Moloy T. Goswami Nicholas Miller Eric Weh Sraboni Chaudhury Li Zhang Anthony Andren Heather Hager Katherine M. Weh Costas A. Lyssiotis Costas A. Lyssiotis Costas A. Lyssiotis Cagri G. Besirli Thomas J. Wubben |
| author_sort | Shubha Subramanya |
| collection | DOAJ |
| description | Photoreceptor cell death is the cause of vision loss in many forms of retinal disease. Metabolic dysfunction within the outer retina has been shown to be an underlying factor contributing to photoreceptor loss. Therefore, a comprehensive understanding of the metabolic pathways essential to photoreceptor health and function is key to identifying novel neuroprotective strategies. Glutamic-oxaloacetic transaminase 1 (Got1) encodes for a cytosolic aspartate aminotransferase that reversibly catalyzes the transfer of an amino group between glutamate and aspartate and is an important aspect of the malate-aspartate shuttle (MAS), which transfers reducing equivalents from the cytosol to the mitochondrial matrix. Previous work has demonstrated that the activity of this enzyme is highest in photoreceptor inner segments. Furthermore, ex vivo studies have demonstrated that the retina relies on aspartate aminotransferase for amino acid metabolism. Importantly, aspartate aminotransferase has been suggested to be an early biomarker of retinal degeneration in retinitis pigmentosa and a possible target for neuroprotection. In the present study, we characterized the effect of Got1 deletion on photoreceptor metabolism, function, and survival in vivo by using a rod photoreceptor-specific, Got1 knockout mouse model. Loss of the GOT1 enzyme from rod photoreceptors resulted in age-related photoreceptor degeneration with an accumulation of retinal aspartate and NADH and alterations in the expression of genes involved in the MAS, the tricarboxylic acid (TCA) cycle, and redox balance. Hence, GOT1 is critical to in vivo photoreceptor metabolism, function, and survival. |
| first_indexed | 2024-03-09T02:55:56Z |
| format | Article |
| id | doaj.art-45ce965be4f045d3b05edbc90670c130 |
| institution | Directory Open Access Journal |
| issn | 2674-0826 |
| language | English |
| last_indexed | 2024-03-09T02:55:56Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Ophthalmology |
| spelling | doaj.art-45ce965be4f045d3b05edbc90670c1302023-12-05T04:45:14ZengFrontiers Media S.A.Frontiers in Ophthalmology2674-08262023-12-01310.3389/fopht.2023.13060191306019Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degenerationShubha Subramanya0Moloy T. Goswami1Nicholas Miller2Eric Weh3Sraboni Chaudhury4Li Zhang5Anthony Andren6Heather Hager7Katherine M. Weh8Costas A. Lyssiotis9Costas A. Lyssiotis10Costas A. Lyssiotis11Cagri G. Besirli12Thomas J. Wubben13Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United StatesRogel Cancer Center, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United StatesPhotoreceptor cell death is the cause of vision loss in many forms of retinal disease. Metabolic dysfunction within the outer retina has been shown to be an underlying factor contributing to photoreceptor loss. Therefore, a comprehensive understanding of the metabolic pathways essential to photoreceptor health and function is key to identifying novel neuroprotective strategies. Glutamic-oxaloacetic transaminase 1 (Got1) encodes for a cytosolic aspartate aminotransferase that reversibly catalyzes the transfer of an amino group between glutamate and aspartate and is an important aspect of the malate-aspartate shuttle (MAS), which transfers reducing equivalents from the cytosol to the mitochondrial matrix. Previous work has demonstrated that the activity of this enzyme is highest in photoreceptor inner segments. Furthermore, ex vivo studies have demonstrated that the retina relies on aspartate aminotransferase for amino acid metabolism. Importantly, aspartate aminotransferase has been suggested to be an early biomarker of retinal degeneration in retinitis pigmentosa and a possible target for neuroprotection. In the present study, we characterized the effect of Got1 deletion on photoreceptor metabolism, function, and survival in vivo by using a rod photoreceptor-specific, Got1 knockout mouse model. Loss of the GOT1 enzyme from rod photoreceptors resulted in age-related photoreceptor degeneration with an accumulation of retinal aspartate and NADH and alterations in the expression of genes involved in the MAS, the tricarboxylic acid (TCA) cycle, and redox balance. Hence, GOT1 is critical to in vivo photoreceptor metabolism, function, and survival.https://www.frontiersin.org/articles/10.3389/fopht.2023.1306019/fullphotoreceptorGOT1malate-aspartate shuttleredoxTCA cyclemetabolism |
| spellingShingle | Shubha Subramanya Moloy T. Goswami Nicholas Miller Eric Weh Sraboni Chaudhury Li Zhang Anthony Andren Heather Hager Katherine M. Weh Costas A. Lyssiotis Costas A. Lyssiotis Costas A. Lyssiotis Cagri G. Besirli Thomas J. Wubben Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration Frontiers in Ophthalmology photoreceptor GOT1 malate-aspartate shuttle redox TCA cycle metabolism |
| title | Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration |
| title_full | Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration |
| title_fullStr | Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration |
| title_full_unstemmed | Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration |
| title_short | Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration |
| title_sort | rod photoreceptor specific deletion of cytosolic aspartate aminotransferase got1 causes retinal degeneration |
| topic | photoreceptor GOT1 malate-aspartate shuttle redox TCA cycle metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fopht.2023.1306019/full |
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