Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd..
Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Aging cell - 22(2023), 7 vom: 25. Juli, Seite e13852 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mishra, Saurabh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.07.2023 Date Revised 03.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/acel.13852 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Mishra, Saurabh |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation |
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| 500 | |a Date Revised 03.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. | ||
| 520 | |a Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a human inducible pluripotent stem cells | |
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| 700 | 1 | |a Karthikeyan, Manikandan |e verfasserin |4 aut | |
| 700 | 1 | |a Bellar, Annette |e verfasserin |4 aut | |
| 700 | 1 | |a Musich, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Shashi Shekhar |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dongmei |e verfasserin |4 aut | |
| 700 | 1 | |a Sekar, Jinendiran |e verfasserin |4 aut | |
| 700 | 1 | |a Attaway, Amy H |e verfasserin |4 aut | |
| 700 | 1 | |a Chelluboyina, Aruna Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Lorkowski, Shuhui Wang |e verfasserin |4 aut | |
| 700 | 1 | |a Roychowdhury, Sanjoy |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Willard, Belinda |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Jonathan D |e verfasserin |4 aut | |
| 700 | 1 | |a Hoppel, Charles L |e verfasserin |4 aut | |
| 700 | 1 | |a Vachharajani, Vidula |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Avinash |e verfasserin |4 aut | |
| 700 | 1 | |a Dasarathy, Srinivasan |e verfasserin |4 aut | |
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