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

Xiu-Fei Chen1,2,3, Meng-Xin Tian4,5, Ren-Qiang Sun1,2,3

  • 1Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China.

EMBO Reports
|March 2, 2018
PubMed

Insights

Sirtuin 5 (SIRT5) deacetylase inhibits acyl-CoA oxidase 1 (ACOX1) activity in peroxisomes. SIRT5 prevents oxidative stress and hepatocellular carcinoma (HCC) by regulating ACOX1, revealing a new role in liver protection.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Peroxisomes are major contributors to cellular hydrogen peroxide (H2O2) production.
  • Acyl-CoA oxidase 1 (ACOX1), a key enzyme in fatty acid oxidation, is a significant H2O2 producer and its dysfunction is linked to liver disease and cancer.

Purpose of the Study:

  • To investigate the role of sirtuin 5 (SIRT5) in regulating peroxisomal function and oxidative stress.
  • To elucidate the mechanism by which SIRT5 affects ACOX1 activity and its implications in hepatocellular carcinoma (HCC).

Main Methods:

  • Immunofluorescence to confirm SIRT5 localization in peroxisomes.
  • Biochemical assays to assess ACOX1 activity and succinylation levels.
  • Cellular and mouse models to study the effects of SIRT5 deletion and ACOX1 knockdown on H2O2 production and DNA damage.

Main Results:

  • SIRT5 directly interacts with and desuccinylates ACOX1 within peroxisomes.
  • SIRT5-mediated desuccinylation inhibits ACOX1 activity by preventing dimer formation, thereby reducing H2O2 generation.
  • SIRT5 deficiency leads to increased oxidative stress and DNA damage, while SIRT5 upregulation is observed in HCC, correlating with increased ACOX1 activity.

Conclusions:

  • SIRT5 acts as a novel regulator of peroxisomal oxidative stress by inhibiting ACOX1 activity.
  • SIRT5 plays a protective role in the liver and suppresses HCC development.
  • Targeting the SIRT5-ACOX1 axis may offer therapeutic strategies for liver diseases and HCC.
Keywords:
ACOX1SIRT5liver canceroxidative stresssuccinylation

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