Sirtuin 3 (SIRT3) Protein Regulates Long-chain Acyl-CoA Dehydrogenase by Deacetylating Conserved Lysines Near the Active Site

Bharathi, Sivakama S.; Zhang, Yuxun; Mohsen, Al‐Walid; Uppala, Radha; Balasubramani, Manimalha; Schreiber, Emanuel M.; Uechi, Guy; Beck, Megan E.; Rardin, Matthew J.; Vockley, Jerry; Verdin, Eric; Gibson, Bradford W.; Hirschey, Matthew D.; Goetzman, Eric S.

doi:10.1074/jbc.m113.510354

Cited by 158 publications

(121 citation statements)

References 38 publications

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“…These data support the evidence showing increased fatty acid oxidation in the presence of excess fat and mitochondrial protein acetylation (8,9). Contrasting studies also show that the direct deacetylation of lysine residues on the fatty acid oxidation enzymes themselves can activate metabolic activity (5,6). Whether this reflects differential regulation of the same metabolic pathway at the levels of protein folding and enzyme activity is an intriguing concept that requires clarification.…”

Section: Discussionsupporting

confidence: 66%

“…On one hand, the mitochondrial sirtuin SIRT3 targets numerous enzymes involved in fat oxidation. Here SIRT3 deacetylates and activates long-chain acylCoA dehydrogenase and medium-chain acyl-CoA dehydrogenase (MCAD) 3 (5,6). In parallel, under dietary restricted conditions, multiple fatty acid oxidation enzymes show increased lysine residue deacetylation in control versus SIRT3 knockout mice, and SIRT3 null mice have increased accumula-tion of acylcarnitines, a finding consistent with reduced fat oxidation (7).…”

mentioning

confidence: 54%

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Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Chen

Aponte

et al. 2015

Journal of Biological Chemistry

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Background: A distinct mechanism linking fasting-associated mitochondrial protein acetylation and increased fat oxidation is unknown. Results: Acetylation of heat shock protein 10 enhances medium-chain acyl-CoA dehydrogenase folding, enzyme activity, and fat oxidation. Conclusion: A novel acetylation-dependent mechanism modulates fat oxidation via regulating mitochondrial metabolic enzyme folding. Significance: A Sirtuin 3 deacetylase-linked mechanism to control fat oxidation via modulation of enzyme folding has been identified.

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 54%

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Chen

Aponte

et al. 2015

Journal of Biological Chemistry

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“…However, both enzymatic assays are reported to provide comparable results in medium-chain acylCoA dehydrogenase-deficient patients (24). On the other hand, some specific acetylation sites are shown to change the activity by modulating the conformation of the LCAD active site (2). This suggests that the impact of LCAD acetylation on its activity is, at least in part, due to a site-specific manner, and, as such, the discrepant findings between acetylation and fatty acid ␤-oxidation might be explained by the difference in specific acetylation site controlling metabolic enzymes.…”

Section: H354mentioning

confidence: 97%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, Rebeyka IM, Kantor PF, Lopaschuk GD. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol 311: H347-H363, 2016. First published June 3, 2016; doi:10.1152/ajpheart.00900.2015.-Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid ␤-oxidation rates increased in 21-day vs. 1-and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and ␤-hydroxyacylCoA dehydrogenase (␤-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid ␤-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and ␤-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator-1␣, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxiainducible factor-1␣, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.Listen to this article's corresponding podcast at http://ajpheart.podbean. com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/. myocardial fatty acid oxidation; lysine acetylation; lysine succinylation; newborn heart NEW & NOTEWORTHYThe present study is the first showing that alterations in acetylation and succinylation control of metabolic enzymes contribute to the dramatic shift in cardiac energy metabolism from glycolysis to fatty acid ␤-oxidation seen during maturation. Our results suggest that lysine acetylation enhances cardiac fatty acid ␤-oxidation and inhibits glycolysis during maturation.OVER 1% OF NEWBORNS ARE DIAGNOSED with congenital heart disease (CHD), with one-third of these needing surgery within the first months of life (36). Despite the major advance...

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“…3B). Our previous work using chemically acylated proteins as substrates for recombinant sirtuins has shown that SIRT3 and SIRT5 have highly specific target sites and will not deacylate lysine residues indiscriminately (1,16). Therefore, we used our succinyl-CoA-treated membrane protein fraction as substrate for recombinant SIRT5 to unveil potential target proteins/pathways.…”

Section: Sirt5 Counteracts Succinylation Of Mitochondrial Membrane Prmentioning

confidence: 99%

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

Zhang

Bharathi

Rardin

et al. 2017

Journal of Biological Chemistry

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Edited by George M. Carman SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. In vitro, succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Mitochondrial oxidative energy metabolism is fundamental to human health, and changes in mitochondrial function are now recognized as playing an etiological role in diseases such as cancer, diabetes, and neurodegeneration. Of particular importance to mitochondrial function are the ϳ200 proteins that reside on the inner mitochondrial membrane (IMM).3 IMM proteins include a large family of solute transporters, several ion channels, four electron transport chain (ETC) complexes, and ATP synthase. Additionally, the IMM has many peripherally associated proteins that bind to the membrane electrostatically rather than via transmembrane domains. This group includes enzymes such as carnitine palmitoyltransferase-2, mitochondrial trifunctional protein (MTP), and very-longchain acyl-CoA dehydrogenase (VLCAD), which together catalyze long-chain fatty acid oxidation (FAO). All three show membrane localization through electrostatic binding to cardiolipin on the IMM (1-3). Cardiolipin also appears to facilitate assembly of higher-order ETC "supercomplexes" that mediate maximal respiratory efficiency (4). In an additional layer of complexity, there is increasing evidence that metabolic pathways that directly produce reducing equivalents, such as FAO and the tricarboxylic acid cycle (TCA), can physically interact with the ETC and potentially with each other (5).To date, the factors that regulate metabolic complex assembly and facilitate protein-protein and protein-lipid interactions on the IMM are poorly understood. Reversible post-translational protein modifications such as lysine acylation are widespread in the mitochondria and represent a potential regulatory mechanism for the formation and function of IMM protein complexes. For example, we recently showed that succinylation of three lysine residues in the VLCAD C terminus leads to a complete loss of membrane binding (1). Succinylation converts the positively charged lysine residues to negative charges, thereby disrupting the electrostatic interaction between the amphipathic helix of VLCAD and cardiolipin. Incubation with the mitochondrial desuccinylase SIRT5 restores membrane binding of VLCAD. Mass spectrometry studies have identified SIRT5-targeted lysines on other IMM proteins such as MTP, ADP/ATP translocase, isocitrate dehydrogenase, and hydroxymethylglutaryl-CoA synthase-2 (6 -10), but its role in maintaining the integrity of the IMM proteome has not been directly

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Sirtuin 3 (SIRT3) Protein Regulates Long-chain Acyl-CoA Dehydrogenase by Deacetylating Conserved Lysines Near the Active Site

Cited by 158 publications

References 38 publications

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

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