4.8 Article

Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions

Journal

EMBO JOURNAL
Volume 34, Issue 21, Pages 2620-2632

Publisher

WILEY
DOI: 10.15252/embj.201591271

Keywords

acetylation; mass spectrometry; proteomics; SIRT3; stoichiometry

Funding

  1. Novo Nordisk Foundation [NNF14CC0001]
  2. Austrian Science Fund (FWF) [F 3002] Funding Source: researchfish
  3. Novo Nordisk Fonden [NNF14OC0008541] Funding Source: researchfish
  4. Novo Nordisk Foundation Center for Protein Research [PI Chunaram Choudhary] Funding Source: researchfish

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Acetylation is frequently detected on mitochondrial enzymes, and the sirtuin deacetylase SIRT3 is thought to regulate metabolism by deacetylating mitochondrial proteins. However, the stoichiometry of acetylation has not been studied and is important for understanding whether SIRT3 regulates or suppresses acetylation. Using quantitative mass spectrometry, we measured acetylation stoichiometry in mouse liver tissue and found that SIRT3 suppressed acetylation to a very low stoichiometry at its target sites. By examining acetylation changes in the liver, heart, brain, and brown adipose tissue of fasted mice, we found that SIRT3-targeted sites were mostly unaffected by fasting, a dietary manipulation that is thought to regulate metabolism through SIRT3-dependent deacetylation. Globally increased mitochondrial acetylation in fasted liver tissue, higher stoichiometry at mitochondrial acetylation sites, and greater sensitivity of SIRT3-targeted sites to chemical acetylation invitro and fasting-induced acetylation invivo, suggest a nonenzymatic mechanism of acetylation. Our data indicate that most mitochondrial acetylation occurs as a low-level nonenzymatic protein lesion and that SIRT3 functions as a protein repair factor that removes acetylation lesions from lysine residues. s in wild-type mice.

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