Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease |
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Authors: | Wang Hongxia Song Pingping Du Lei Tian Weili Yue Wen Liu Min Li Dengwen Wang Bin Zhu Yushan Cao Cheng Zhou Jun Chen Quan |
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Institution: | Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China. |
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Abstract: | Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease. |
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Keywords: | E3 Ubiquitin Ligase Mitochondria Parkinson Disease Protein-Protein Interactions Ubiquitination Drp1 (Dynamin-related Protein 1) |
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