SIRT3 regulates fatty acid oxidation via reversible enzyme deacetylation

By M. Hirschey, Tadahiro Shimazu, E. Goetzman, Enxuan Jing, B. Schwer, D. Lombard, Carrie A. Grueter, C. Harris, Sudha B. Biddinger, O. Ilkayeva and 10 more. Nature, 2010

991 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/65e4ff46ff5f7ec355baa77f7041f0e5056aebc0

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In Geriatrics and Gerontology

1. E. Verdin
2. M. Haigis
3. Liangyou Rui
4. Huafeng Zhang
5. Ping Gao
6. Linchong Sun
7. Wei Yu
8. F. Alt

In Physiology

1. E. Verdin
2. Liangyou Rui
3. M. Haigis
4. Huafeng Zhang
5. Ping Gao
6. Linchong Sun
7. Christopher B. Newgard
8. Wei Yu

Citations in the corpus

• Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. (2013, background): “, 2012), long-chain-specific acyl-CoA dehydrogenase (ACADL) lysine 42 (Hirschey et al., 2010); and super oxide dismutase (SOD2) lysines 68, 122, and 130 (Chen et al.”
• SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome (2011, positive): “Previous studies show that SIRT3 regulates fatty acid oxidation by reversibly deacetylating proteins in the fatty acid oxidation pathway, such as LCAD, and ablation of SIRT3 increases LCAD acetylation and reduces LCAD activity (Hirschey et al., 2010).”
• PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism (2020, background): “Accordingly, chronic high-fat diet lowers hepatic PGC-1α levels in sedentary WT mice, which leads to reduced hepatic mitochondrial respiration [204].”
• Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. (2013, background): “, 2010) and both deacetylates and regulates the function of several mitochondrial proteins in response to fasting and/or CR, including OTC, LCAD, HMGCS2, and IDH2 (Hallows et al., 2011; Hirschey et al., 2010; Shimazu et al., 2010; Someya et al., 2010).”
• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “The transition to fasting enhances both the cellular NAD level and the SIRT3 expression, which, in turn, catalyzes the deacetylation of LCAD to promote fatty-acid oxidation.(221) SIRT3 orchestrates the metabolism reprogramming via controlling the balance between cytosolic glycolytic metabolism and m”
• Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting (2017, background): “(76–78) Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting such as reduced ATP levels and intolerance to cold exposure.(78) Shimazu et al.”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “Hyperacetylation of LCAD at lysine 42 in SIRT3knockout mice reduced LCAD enzyme activity (Hirschey et al., 2010), and acetylation of lysine residue 318 and 322 of LCAD are two other SIRT3-targeted sites (Bharathi et al., 2013).”
• Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “…by deacetylating phosphoenolpyruvate carboxykinase (Jiang et al., 2011); SIRT3 regulates OXPHOS (Ahn et al., 2008), fatty acid oxidation (Hirschey et al., 2010), ketogenesis (Shimazu et al., 2010), and defense against oxidative stress (Finley et al., 2011; Someya et al., 2010); and…”
• Energy Metabolism in the Liver (2014, positive): “Mitochondrial SIRT3, which is upregulated in the fasted state, deacetylates and activates LCAD in the liver, thus promoting fatty acid β -oxidation (82).”
• Sirtuin Regulation of Mitochondria - Energy Production, Apoptosis, and Signaling (2010, background): “SIRT3 regulates ATP levels in a variety of tissues, suggesting that its activity could have an important role in ATP-mediated retrograde signaling [46,55].”