Parkin-induced ubiquitination of Mff promotes its association with p62/SQSTM1 during mitochondrial depolarization

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 mitochon...

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Published inActa biochimica et biophysica Sinica Vol. 47; no. 7; pp. 522 - 529
Main Authors Gao, Ju, Qin, Siyue, Jiang, Chang'an
Format Journal Article
LanguageEnglish
Published China 01.07.2015
Subjects
Adaptor Proteins, Signal Transducing - metabolism
Autophagy - physiology
HEK293 Cells
Humans
Membrane Potential, Mitochondrial
Membrane Proteins - metabolism
Mitochondrial Proteins - metabolism
Sequestosome-1 Protein
Ubiquitin-Protein Ligases - physiology
Ubiquitination
化促
去极化
泛素连接酶
神经退行性疾病
线粒体
自噬作用
诱导
金
p62/SQSTM1
mitophagy
Mff
ubiquitination
Parkin
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Summary: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 depo- larized 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 pheno- type. 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.
Bibliography: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 depo- larized 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 pheno- type. 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.
31-1940/Q
Parkin, Mff, p62/SQSTM1, mitophagy, ubiquitination
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1672-9145
1745-7270
DOI:10.1093/abbs/gmv044