miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes

doi:10.1016/j.lfs.2021.119415

	miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes
	Tai, Yusi 1,3; Pu, Mei 1,2,3; Yuan, Luyang 4; Guo, Huijie 1,2,3; Qiao, Junwen 1; Lu, Henglei 1; Wang, Guanghui 5,6; Chen, Jing 1; Qi, Xinming 1; Tao, Zhouteng 1
刊名	LIFE SCIENCES
	2021-07-01
卷号	276 页码:13
关键词	Mitophagy PINK1 miR-34a-5p CDS Non-seed region
ISSN号	0024-3205
DOI	10.1016/j.lfs.2021.119415
通讯作者	Tao, Zhouteng(taozhouteng@simm.ac.cn) ; Ren, Jin(jren@cdser.simm.ac.cn)
英文摘要	Aims: PTEN induced putative kinase 1 (PINK1)-mediated mitophagy process is tightly associated with various age-dependent diseases in mammals. The roles of miRNAs (miRNAs) in the PINK1-mediated mitophagy process are not fully understood. Here we discovered that miR-34a-5p suppresses PINK1 expression directly though two post-transcriptional non-classical binding modes, resulting in inhibition of PINK1-mediated mitophagy process. Main methods: For in vivo experiments, brains were dissected from 8 weeks old and 40 weeks old C57BL/6 male mice to measure miR-34a-5p expression and PINK1 expression. For in vitro experiments, overexpression of miR34a-5p mimics in HEK293 cells was performed to investigate the effect of miR-34a-5p on PINK1 expression and its regulatory mechanism, parkin recruitment and mitophagy process. Key findings: The level of miR-34a-5p was upregulated and the level of PINK1 mRNA was downregulated in brains of aged mice. Both the 3?-untranslated region (3?UTR) and the Coding DNA sequence (CDS) of PINK1 mRNA were bound to the non-seed region of miR-34a-5p, rather than the seed region, resulting in a decrease in PINK1 expression. Endogenous miR-34a-5p knockout increased PINK1 expression. Further results indicated that miR34a-5p inhibits mitophagy process by reduction of PINK1. miR-34a-5p hinders phosphorylated Ser65ubiquitin (pS65-Ub) accumulation, prevents the mitochondrial recruitment of Parkin, attenuates ubiquitination and delays the clearance of damaged mitochondria. Significance: We firstly found that miR-34a-5p suppresses PINK1 directly and further regulates mitophagy through non-canonical modes. This finding hints at a crucial role of miR-34a-5p implicated in accelerating the pathogenesis of age-related neurological diseases.
资助项目	National Youthful Natural Science Foundation of China[81701261] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09101001003007] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09201017004] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09732002013] ; Open Research Fund of State Key Laboratory of Transient Optics and Photonics[SKLST201806] ; Shanghai Committee of Science and Technology of China[18DZ2290200]
WOS关键词	MITOCHONDRIAL-FUNCTION ; DAMAGED MITOCHONDRIA ; OXIDATIVE STRESS ; PINK1 ; PARKIN ; UBIQUITIN ; MICRORNA ; TRANSLOCATION ; RECRUITMENT ; SUPPRESSES
WOS研究方向	Research & Experimental Medicine ; Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000647712400002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297413]
专题	中国科学院上海药物研究所
通讯作者	Tao, Zhouteng; Ren, Jin
作者单位	1.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 5.Soochow Univ, Coll Pharmaceut, Jiangsu Key Lab Neuropsychiat Dis, Lab Mol Neuropathol, Suzhou, Peoples R China 6.Soochow Univ, Coll Pharmaceut, Dept Pharmacol, Suzhou, Peoples R China
推荐引用方式 GB/T 7714	Tai, Yusi,Pu, Mei,Yuan, Luyang,et al. miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes[J]. LIFE SCIENCES,2021,276:13.
APA	Tai, Yusi.,Pu, Mei.,Yuan, Luyang.,Guo, Huijie.,Qiao, Junwen.,...&Ren, Jin.(2021).miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes.LIFE SCIENCES,276,13.
MLA	Tai, Yusi,et al."miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes".LIFE SCIENCES 276(2021):13.