Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system.

[inclusion body myositis]

VCP /p 97 is a hexameric ring-shaped AAA (+) ATPase 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 VCPs have higher affinities for several cofactors , including Npl 4 , Ufd 1 and p 47 . 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 Npl 4 and p 47 also migrate to mitochondria after uncoupler treatment , and Npl 4 , Ufd 1 or p 47 silencing causes defective mitochondria clearance after uncoupler treatment . Moreover , pathogenic VCPs show impaired migration to mitochondria , and the exogenous pathogenic VCP expression partially inhibits Npl 4 and p 47 localization to mitochondria . These results suggest that the increased affinities of pathogenic VCPs for these cofactors cause the impaired movement of pathogenic VCPs . In adult flies , exogenous expression of wild-type VCP , but not pathogenic VCPs , reduces the number of abnormal mitochondria in muscles . Failure of pathogenic VCPs to function on damaged mitochondria may be related to the pathogenesis of IBMPFD and ALS .

Diseases
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Diseases presenting "abnormal mitochondria in muscles" symptom

inclusion body myositis

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