Differential requirements for mitochondrial electron transport chain components in the adult murine liver
Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not unde...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/80919 |
| _version_ | 1811179995623587840 |
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| author | Nicholas P Lesner Xun Wang Zhenkang Chen Anderson Frank Cameron J Menezes Sara House Spencer D Shelton Andrew Lemoff David G McFadden Janaka Wansapura Ralph J DeBerardinis Prashant Mishra |
| author_facet | Nicholas P Lesner Xun Wang Zhenkang Chen Anderson Frank Cameron J Menezes Sara House Spencer D Shelton Andrew Lemoff David G McFadden Janaka Wansapura Ralph J DeBerardinis Prashant Mishra |
| author_sort | Nicholas P Lesner |
| collection | DOAJ |
| description | Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC. |
| first_indexed | 2024-04-11T06:44:05Z |
| format | Article |
| id | doaj.art-bc53e8466ccf4687be0151852c83aa36 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T06:44:05Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-bc53e8466ccf4687be0151852c83aa362022-12-22T04:39:25ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.80919Differential requirements for mitochondrial electron transport chain components in the adult murine liverNicholas P Lesner0https://orcid.org/0000-0001-9734-8828Xun Wang1Zhenkang Chen2https://orcid.org/0000-0002-7919-5546Anderson Frank3Cameron J Menezes4https://orcid.org/0000-0001-5759-8099Sara House5Spencer D Shelton6https://orcid.org/0000-0003-1236-5317Andrew Lemoff7https://orcid.org/0000-0002-4943-0170David G McFadden8Janaka Wansapura9Ralph J DeBerardinis10Prashant Mishra11https://orcid.org/0000-0003-2223-1742Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United StatesAdvanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United StatesMitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.https://elifesciences.org/articles/80919mitochondrialiverComplex I |
| spellingShingle | Nicholas P Lesner Xun Wang Zhenkang Chen Anderson Frank Cameron J Menezes Sara House Spencer D Shelton Andrew Lemoff David G McFadden Janaka Wansapura Ralph J DeBerardinis Prashant Mishra Differential requirements for mitochondrial electron transport chain components in the adult murine liver eLife mitochondria liver Complex I |
| title | Differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| title_full | Differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| title_fullStr | Differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| title_full_unstemmed | Differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| title_short | Differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| title_sort | differential requirements for mitochondrial electron transport chain components in the adult murine liver |
| topic | mitochondria liver Complex I |
| url | https://elifesciences.org/articles/80919 |
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