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Different dynamic movements of wild‐type and pathogenic VCP s and their cofactors to damaged mitochondria in a P arkin‐mediated mitochondrial quality control system
Author(s) -
Kimura Yoko,
Fukushi Junpei,
Hori Seiji,
Matsuda Noriyuki,
Okatsu Kei,
Kakiyama Yukie,
Kawawaki Junko,
Kakizuka Akira,
Tanaka Keiji
Publication year - 2013
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12103
Subject(s) - mitochondrion , biology , microbiology and biotechnology , ubiquitin , pink1 , amyotrophic lateral sclerosis , pathogenesis , autophagy , mitophagy , gene , genetics , immunology , disease , medicine , apoptosis
VCP /p97 is a hexameric ring‐shaped AAA + ATP ase that participates in various ubiquitin‐associated cellular functions. Mis‐sense mutations in VCP gene are associated with the pathogenesis of two inherited diseases: inclusion body myopathy associated with Paget's disease of the bone and front‐temporal dementia ( IBMPFD ) and familial amyotrophic lateral sclerosis ( ALS ). These pathogenic VCP s have higher affinities for several cofactors, including Npl4, Ufd1 and p47. In Parkin‐dependent mitochondrial quality control systems, VCP migrates to damaged mitochondria (e.g., those treated with uncouplers) to aid in the degradation of mitochondrial outer membrane proteins and to eliminate mitochondria. We showed that endogenous Npl4 and p47 also migrate to mitochondria after uncoupler treatment, and Npl4, Ufd1 or p47 silencing causes defective mitochondria clearance after uncoupler treatment. Moreover, pathogenic VCP s show impaired migration to mitochondria, and the exogenous pathogenic VCP expression partially inhibits Npl4 and p47 localization to mitochondria. These results suggest that the increased affinities of pathogenic VCP s for these cofactors cause the impaired movement of pathogenic VCP s. In adult flies, exogenous expression of wild‐type VCP , but not pathogenic VCP s, reduces the number of abnormal mitochondria in muscles. Failure of pathogenic VCP s to function on damaged mitochondria may be related to the pathogenesis of IBMPFD and ALS .