NDP52 SUMOylation contributes to low‐dose X‐rays‐induced cardiac hypertrophy through PINK1/Parkin‐mediated mitophagy via MUL1/SUMO2 signalling

作者：Anbo Gao, Mengjie Wang, Xing Tang, Gang-qing Shi, Kai Hou, Jinren Fang, Linlin Zhou, Hong Zhou, Weimin Jiang, Yukun Li, Fan Ouyang · 发表于：Journal of Cellular Physiology · 年份：2023 · DOI：10.1002/jcp.31145 · 被引用次数：16 · 研究领域：Medicine

Radiation‐induced heart damage caused by low‐dose X‐rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL‐IN‐1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification‐based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low‐dose X‐rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co‐IP coupled with LC–MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2‐mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for de...