SIRT 5 inhibits peroxisomal ACOX 1 to prevent oxidative damage and is downregulated in liver cancer

We show that the deacetylase sirtuin 5 is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5

Xiu‐Fei Chen; Meng‐Xin Tian; Ren‐Qiang Sun; Meng‐Li Zhang; Li‐Sha Zhou; Lei Jin; Lei‐Lei Chen; Wen‐Jie Zhou; Kun‐Long Duan; Yu‐Jia Chen; Chao Gao; Zhou‐Li Cheng; Fang Wang; Jin‐Ye Zhang; Yi‐Ping Sun; Hong‐Xiu Yu; Yu‐Zheng Zhao; Yi Yang; Wei‐Ren Liu; Ying‐Hong Shi; Yue Xiong; Kun‐Liang Guan; Dan Ye


Scholarcy highlights

  • Peroxisomes are ubiquitous and highly dynamic organelles, which are involved in the catabolism of very-long-chain fatty acids, branched-chain fatty acids, D-amino acids, polyamines, and the biosynthesis of ether lipids and bile acids
  • We discover that ACOX1 is a physiological substrate of sirtuin 5 as SIRT5-dependent desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation
  • Significant amount of H2O2 is produced during the ACOX1-catalyzed reaction, raising the question how cells balance the need for VLCFA catabolism and control of cellular H2O2 levels and redox homeostasis
  • We found that SIRT5 knockdown, which leads to high H2O2 accumulation, increased anchorage-independent growth of HepG2 cells, and this effect of SIRT5 loss was blunted by depletion of ACOX1
  • We discover for the first time to our knowledge that SIRT5 is localized in the peroxisome except other subcellular compartments previously reported
  • Another uniqueness of this study is that we show ACOX1, as a rate-limiting enzyme involved in peroxisomal fatty acid b-oxidation, is a physiological substrate of SIRT5, and that SIRT5-mediated lysine desuccinylation causes enzymatic inhibition of ACOX1 by impairing its active dimer formation
  • It is possible that catalytic inhibition of sirtuin 5, due to lack of NAD+, may contribute to the observed increased lysine succinylation and enzyme activation of ACOX1 in hepatocellular carcinoma tissues

Need more features? Save interactive summary cards to your Scholarcy Library.