Regulation of Succinate Dehydrogenase Activity by SIRT3 in Mammalian Mitochondria
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TLDR
The findings constitute the first evidence of the regulation of Complex II activity by the reversible acetylation of the SdhA subunit as a novel substrate of the NAD(+)-dependent deacetylase, SIRT3.Abstract:
A member of the sirtuin family of NAD(+)-dependent deacetylases, SIRT3, is identified as one of the major mitochondrial deacetylases located in mammalian mitochondria responsible for deacetylation of several metabolic enzymes and components of oxidative phosphorylation Regulation of protein deacetylation by SIRT3 is important for mitochondrial metabolism, cell survival, and longevity In this study, we identified one of the Complex II subunits, succinate dehydrogenase flavoprotein (SdhA) subunit, as a novel SIRT3 substrate in SIRT3 knockout mice Several acetylated Lys residues were mapped by tandem mass spectrometry, and we determined the role of acetylation in Complex II activity in SIRT3 knockout mice In agreement with SIRT3-dependent activation of Complex I, we observed that deacetylation of the SdhA subunit increased the Complex II activity in wild-type mice In addition, we treated K562 cell lines with nicotinamide and kaempferol to inhibit deacetylase activity of SIRT3 and stimulate SIRT3 expression, respectively Stimulation of SIRT3 expression decreased the level of acetylation of the SdhA subunit and increased Complex II activity in kaempherol-treated cells compared to control and nicotinamide-treated cells Evaluation of acetylated residues in the SdhA crystal structure from porcine and chicken suggests that acetylation of the hydrophilic surface of SdhA may control the entry of the substrate into the active site of the protein and regulate the enzyme activity Our findings constitute the first evidence of the regulation of Complex II activity by the reversible acetylation of the SdhA subunit as a novel substrate of the NAD(+)-dependent deacetylase, SIRT3read more
Citations
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SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization
Lydia W.S. Finley,Arkaitz Carracedo,Jaewon J. Lee,Amanda Souza,Ainara Egia,Jiangwen Zhang,Julie Teruya-Feldstein,Paula I. Moreira,Sandra M. Cardoso,Clary B. Clish,Pier Paolo Pandolfi,Marcia C. Haigis +11 more
TL;DR: It is shown that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect, and it is found that Sirt3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.
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The world of protein acetylation
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Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.
TL;DR: Findings have shed light on how the mitochondrial sirtuins function in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis and intracellular signaling.
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Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism
Rubén Nogueiras,Kirk M. Habegger,Nilika Chaudhary,Brian Finan,Alexander S. Banks,Marcelo O. Dietrich,Tamas L. Horvath,David A. Sinclair,Paul T. Pfluger,Matthias H. Tschöp +9 more
TL;DR: The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes as mentioned in this paper.
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The updated biology of hypoxia‐inducible factor
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