SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

EMBO Rep. 2018 May;19(5):e45124. doi: 10.15252/embr.201745124. Epub 2018 Feb 28.


Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

Keywords: ACOX1; SIRT5; liver cancer; oxidative stress; succinylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase / antagonists & inhibitors*
  • Acyl-CoA Oxidase / genetics
  • Acyl-CoA Oxidase / metabolism*
  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • DNA Damage
  • Down-Regulation
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Hydrogen Peroxide
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Oxidation-Reduction
  • Oxidative Stress*
  • Peroxisomes / chemistry
  • Prognosis
  • Sirtuins / genetics
  • Sirtuins / metabolism*


  • SIRT5 protein, mouse
  • Hydrogen Peroxide
  • ACOX1 protein, mouse
  • Acyl-CoA Oxidase
  • SIRT5 protein, human
  • Sirtuins