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Abstract |
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| Vol 47 No. 7: 522-529 |
[PDF] [Full Text] |
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| Parkin-induced ubiquitination of Mff promotes its association with p62/SQSTM1 during mitochondrial depolarization |
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| Ju Gao1,2,3,4,
Siyue Qin1,2 and
Chang'an Jiang1,2,3,4,*
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1Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Chengdu 610041, China
2Department of Pediatrics, West China 2nd University Hospital, Sichuan University, Chengdu 610041, China
3Key Laboratory for Molecular Biology of Neural Development, 1068 Xueyuan Blvd., Shenzhen 518055, China
4Institute of Biomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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Abstract The ubiquitin ligase Parkin and autophagic adapter protein p62 are known to function in a common pathway controlling mitochondrial autophagy (mitophagy). However, the evidence supporting that p62 is directly recruited by ubiquitinated proteins remains undetermined. Here, we demonstrate that mitochondrial fission factor (Mff) associates with Parkin and carbonyl cyanide m-chlorophenyl hydrazone treatment significantly increases the affinity of Parkin with Mff. After recruitment to depolarized mitochondria, Parkin mediates poly-ubiquitination of Mff at lysine 251. Replacement of lysine 251 by arginine (K251R) totally abrogates Parkin-stimulated ubiquitination of Mff. Subsequently, the ubiquitinated Mff promotes its association with p62. Mff knockout interferes with p62 translocation to damaged mitochondria. Only re-transfection of Mff WT, but not K251R mutant, rescues this phenotype. Furthermore, loss of Mff results in failure of Parkin translocation and final clearance of damaged mitochondria. Thus, our data reveal functional links among Mff, p62, and the selective autophagy of mitochondria, which are implicated in the pathogenesis of neurodegeneration diseases. |
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Keywords Parkin; Mff; p62/SQSTM1; mitophagy; ubiquitination |
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Received 2014-12-5
Accepted 2015-5-4 |
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Funding This work was supported by the grants from the National Basic Research Program of China (973 Program) (No. 2009CB941404 to C.J.), the National Natural Science Foundation of China (No. 30871032 to C.J.), and the Hundred Talent Program of the Chinese Academ |
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* Correspondence address Tel/Fax: +86-28-85503905; E-mail: [email protected] |
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