The Effect Of Parkinson’s Disease Associated Mutant VPS35 On Mitochondrial Function And Assembly

Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson’s disease(PD)and expanding evidences demonstrate that impaired assembly of mitochondrial complex and mitochondrial dynamics are important mechanisms leading to mitochondrial and neuronal dysfunction/degeneration.In this study,we investigated whether vacuolar sorting protein 35(VPS35)is involved in the regulation of mitochondrial complex assembly and function in primary human dermal fibroblasts and M17 cell lines.In fibroblasts from one patient bearing with VPS35 D620 N mutation,the electron transport chain(ETC)complex Ⅰ and Ⅱ dependent respiration is significantly reduced.This reduction is the result of reduced enzymatic activity of complex Ⅰand complex Ⅱ.Further investigation of the ETC complex integrity in fibroblasts and M17 cell lines indicates that the reduced EC enzymatic activity results from disassembly of ETC complex and can be rescued by inhibition of mitochondrial fission.Moreover,inhibition of mitochondrial fission can also rescue bioenergetics defects investigated in our models.Taken together,these studies suggest that mutation of VPS35 impairs assembly of the ETC complexes,leading to abnormal bioenergetics,which can be rescued by inhibition of mitochondrial fission.