线粒体
生物
粒体自噬
品脱1
泛素
肌萎缩侧索硬化
发病机制
细胞生物学
自噬
基因
遗传学
免疫学
疾病
内科学
细胞凋亡
医学
作者
Yoko Kimura,Junpei Fukushi,Seiji Hori,Noriyuki Matsuda,Kei Okatsu,Yukie Kakiyama,Junko Kawawaki,Akira Kakizuka,Keiji Tanaka
出处
期刊:Genes to Cells
[Wiley]
日期:2013-11-12
卷期号:18 (12): 1131-1143
被引量:38
摘要
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 .
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