期刊
EMBO REPORTS
卷 19, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/embr.201745124
关键词
ACOX1; liver cancer; oxidative stress; SIRT5; succinylation
资金
- National Key RAMP
- D Program of China [2016YFA0501800]
- NSFC [81372198]
- 973 Program [2015CB910401]
- Shanghai Committee of Science and Technology, China [16JC1404000]
- NIH [GM067113, CA063834, CA196878, GM51586]
Peroxisomes account for similar to 35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid beta-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.
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