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SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation
Open accessAbstract
Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.
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In the citing paper
“Sirt3 is an established deacetylase whose targets include long chain acyl CoA dehydrogenase (LCAD), succinate dehydrogenase and Mn superoxide dismutase (SOD2) (Hirschey et al., 2010; Qiu et al., 2010).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Hirschey et al., 2010
In the citing paper
“Additionally, higher NAD+ levels can promote the deacetylase and deacylase activity of both nuclear SIRT1 and mitochondrial SIRT3, which regulate mitochondrial function and protect from high-fat diet-induced metabolic disease42,81,85–88.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [85]
In the citing paper
“Loss of SIRT3 has been shown to inhibit fatty acid oxidation ((Hirschey et al. 2010)); the same study showed decreased gluconeogenic production of glucose in response to cold challenge and decreased production of the ketone body beta-hydroxybutyrate during fasting.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“Loss of SIRT3 has been shown to inhibit fatty acid oxidation ((Hirschey et al. 2010)); the same study showed decreased gluconeogenic production of glucose in response to cold challenge and decreased production of the ketone body beta-hydroxybutyrate during fasting.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“SIRT3 is upregulated during fasting (Hirschey et al. 2010) and more generally by PGC-1α (Kong et al. 2010), which allows it to best control the hyperacetylation caused by acetyl-CoA-dependent metabolic processes such as fatty acid oxidation and ketone body metabolism.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“These mice also share other characteristics of human disorders of fatty acid oxidation, including cold intolerance and reduced basal ATP levels ((Hirschey et al. 2010)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“SIRT3 promotes the efficient utilization of lipids as a primary source of acetyl-CoA during fasting by activating long-chain acyl-CoA dehydrogenase, a key enzyme in the β-oxidation of fatty acids, via deacetylation at K42 ((Hirschey et al. 2010)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“Mice lacking SIRT3 accumulate β-oxidation precursors and intermediates, including triglycerides and long-chain fatty acids.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Hirschey et al. 2010
In the citing paper
“In mice, SIRT3 is normally upregulated during fasting in liver and brown fat where it plays a role in fatty-acid oxidation by maintaining the deacetylation of long-chain acyl coenzyme A dehydrogenase in mitochondria (175).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [175]
In the citing paper
“In its absence, SIRT3-deficient mice show reduced utilization of lipid stores during fasting: they have decreased fatty acid oxidation, accumulate triglycerides, and have diminished production of hepatic ATP.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [175]
In the citing paper
“Upon fasting, SIRT3 expression is rapidly induced and deacetylates key residues on mitochondrial proteins (Hirschey et al, 2010).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Hirschey et al, 2010
In the citing paper
“One week of HFD enhanced SIRT3 levels and prevented mitochondrial hyperacetylation despite the higher levels of lipid substrates (Hirschey et al, 2010).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Hirschey et al, 2010
In the citing paper
“Dietary excess of lipids also dramatically changes mitochondrial protein acetylation.”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Hirschey et al, 2010
In the citing paper
“Conversely, prolonged HFD dramatically decreases SIRT3 expression, correlating with the appearance of mitochondrial hyperacetylation and mitochondrial dysfunction (Hirschey et al, 2010).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Hirschey et al, 2010
In the citing paper
“For instance, acetylation of long-chain fatty acyl-CoA dehydrogenase, one of the four enzymes involved in the mitochondrial fat oxidation pathway, causes its inactivation, leading to fat accumulation [154], [155].”
In the citing paper
“SIRT3 has been reported to regulate mitochondrial fatty acid β-oxidation via deacetylation of long-chain acyl-CoA dehydrogenase, which, when dysregulated, results in defective fatty acid oxidation (Hirschey et al., 2010).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Hirschey et al., 2010
In the citing paper
“which represents a key regulator of mitochondrial energy metabolism (Palacios et al., 2009; Hirschey et al., 2010, 2011; Anderson and Hirschey, 2012).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Hirschey et al., 2010
In the citing paper
“Interestingly, SIRT3 is present in mitochondria, where it regulates the acetylation and activity of a variety of metabolic enzymes, suggesting additional ways that it might affect mitochondrial ROS production 73.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [73]
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Metadata
- Authors
- Hirschey, M. D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D. B., Grueter, C. A., Harris, C., Biddinger, S., Ilkayeva, O. R., Stevens, R. D., Li, Y., Saha, A. K., Ruderman, N. B., Bain, J. R., Newgard, C. B., Farese Jr, R. V., Alt, F. W., Kahn, C. R., & Verdin, E.
- Affiliations
- Gladstone Institutes (US)
- University of Pittsburgh (US)
- Joslin Diabetes Center (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Duke University (US)
- Cell Signaling Technology (United States) (US)
- Boston University (US)
- Corresponding author
- Verdin, Eric
- ORCID
- Venue
- Nature
- Published
- 2010-03
- Volume
- 464
- Issue
- 7285
- Pages
- 121-125
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2841477
- OpenAlex
- W2052751736
- Cited by
- 1,687
- References
- 44
- Citations by year
- 2026: 77 · 2025: 86 · 2024: 108 · 2023: 95 · 2022: 125 · 2021: 107 · 2020: 110 · 2019: 112 · 2018: 110 · 2017: 102 · 2016: 127 · 2015: 113 · 2014: 95 · 2013: 110 · 2012: 97
- FWCI
- 40.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01dk019514-35)
- National Institute on Aging (K08AG022325)
- National Heart, Lung, and Blood Institute (P01HL068758)
- National Institute of Diabetes and Digestive and Kidney Diseases (L40 DK065607, R01DK067509, DK59637, U24DK059637, K01DK076573, P30DK026743, R01-DK-019514)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- SIRT3, sirtuins, mitochondrial fatty acid oxidation, protein deacetylation, long-chain acyl-CoA dehydrogenase, acetylation, fasting, liver, brown adipose tissue, cold sensitivity, ATP levels, triglycerides, NAD+-dependent deacetylase, metabolic stress, caloric restriction
- MeSH terms
- Acetylation, Adenosine Triphosphate, Animals, Body Temperature Regulation, Adipose Tissue, Brown, Carnitine, Cell Line, Cold Temperature, Fasting, Fatty Acids, Humans, Hypoglycemia, Liver, Male, Mitochondria, Oxidation-Reduction, Mass Spectrometry, Triglycerides, Up-Regulation, Caloric Restriction, Acyl-CoA Dehydrogenase, Long-Chain, Mice, Sirtuin 3
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