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

被引：6

作者：

Gao, Anbo ^{[1
]}

Wang, Mengjie ^{[1
]}

Tang, Xing ^{[1
]}

Shi, Gangqing ^{[1
,2
]}

Hou, Kai ^{[1
]}

Fang, Jinren ^{[1
]}

Zhou, Linlin ^{[1
]}

Zhou, Hong ^{[3
]}

Jiang, Weimin ^{[4
]}

Li, Yukun ^{[5
]}

Ouyang, Fan ^{[4
]}

机构：

[1] Univ South China, Affiliated Hosp 2, Clin Res Inst, Hengyang Med Sch, Hengyang, Hunan, Peoples R China

[2] Univ South China, Canc Res Inst, Hengyang Med Sch, Hunan Prov Key Lab Tumor Cellular & Mol Pathol, Hengyang, Hunan, Peoples R China

[3] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Radiol, Hengyang, Hunan, Peoples R China

[4] Cent South Univ, Zhuzhou Cent Hosp, Xiangya Hosp Zhuzhou, Dept Cardiol, Zhuzhou, Peoples R China

[5] Cent South Univ, Xiangya Hosp Zhuzhou, Zhuzhou Cent Hosp, Dept Assisted Reprod Ctr, Zhuzhou, Peoples R China

来源：

JOURNAL OF CELLULAR PHYSIOLOGY | 2024年 / 239卷 / 01期

基金：

中国国家自然科学基金;

关键词：

mitophagy; MUL1; NDP52; PINK1/Parkin; radiation-induced heart damage; SUMOylation; AUTOPHAGY; TARGETS; DISEASE;

D O I：

10.1002/jcp.31145

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 NDP52(K262R) inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52(K262R) 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 NDP52(K262R) 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 degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.

引用

页码：79 / 96

页数：18