| Literature DB >> 29491006 |
Xiu-Fei Chen1,2,3, Meng-Xin Tian4,5, Ren-Qiang Sun1,2,3, Meng-Li Zhang1,2,3, Li-Sha Zhou1,2,3, Lei Jin4,5, Lei-Lei Chen1,2,3, Wen-Jie Zhou1,2,3, Kun-Long Duan1,2,3, Yu-Jia Chen1,2,3, Chao Gao1,2,3, Zhou-Li Cheng1,2,3, Fang Wang1,2,3, Jin-Ye Zhang1,2,3, Yi-Ping Sun1,2,3, Hong-Xiu Yu1,2,3, Yu-Zheng Zhao6, Yi Yang6, Wei-Ren Liu4,5, Ying-Hong Shi4,5, Yue Xiong1,2,3,7, Kun-Liang Guan1,2,3,8, Dan Ye9,2,3,10.
Abstract
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.Entities:
Keywords: ACOX1; SIRT5; liver cancer; oxidative stress; succinylation
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Year: 2018 PMID： 29491006 PMCID： PMC5934778 DOI： 10.15252/embr.201745124
Source DB: PubMed Journal: EMBO Rep ISSN： 1469-221X Impact factor: 8.807