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Role of Mitophagy in Hereditary Parkinson's Disease Noriyuki Matsuda 1 , Keiji Tanaka 1 , Masaaki Komatsu 2 1Laboratory of Protein Metabolism,Tokyo Metropolitan Institute of Medical Science 2Protein Metabolism Project,Tokyo Metropolitan Institute of Medical Science Keyword: Parkinson's disease , Mitophagy , PINK1 , Parkin , membrane potential pp.279-285
Published Date 2012/3/1
DOI https://doi.org/10.11477/mf.1416101147
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Abstract

 Parkinson's disease (PD) is the second most common neurodegenerative disease. The majority of PD cases are sporadic; however,the discovery of genes linked to rare familial forms of the disease has provided crucial insight into the molecular mechanisms of disease pathogenesis. PINK1 and PARKIN are causal genes for hereditary (i. e.,autosomal recessive) early-onset PD. In 2010,intense efforts by our laboratory and several other groups have revealed the mechanism by which PINK1 and Parkin maintain mitochondrial integrity. The essence of the model is that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential (ΔΨm)-dependent manner and that a loss in ΔΨm stabilizes PINK1 on damaged mitochondria,and then recruits Parkin from the cytosol to the mitochondria for proteasomal and autophagic degradation. Recently,a pharmacological approach using various chemical reagents such as valinomycin,nigericin,2-deoxy-D-glucose,and oligomycin demonstrated that Parkin recruitment is voltage-dependent and independent of changes in ATP or pH. Moreover,F1-ATPase inhibitor azide recruited Parkin to the mitochondria only in ρ0 cells,which lack mtDNA and a functional electron transport chain. These results confirm that ΔΨm is the most important factor for the discrimination of damaged mitochondria from their healthy counterparts. Here we provide an overview of how PINK1 and Parkin identify,label and clear damaged/depolarized mitochondria,focusing on the role of mitochondrial autophagy (mitophagy).


Copyright © 2012, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1344-8129 印刷版ISSN 1881-6096 医学書院

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