title: Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1.
abstract: Mutations in the mitochondrial encoded protein PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson disease (PD). In mammalian cells, mutant PINK1 has been reported to promote fission or inhibit fusion in mitochondria; however, the mechanism by which this process occurs remains elusive. Using an ecdysone-inducible expression system in mammalian dopaminergic neuronal cells, we report here that human mutant PINK1 (L347P and W437X) mediates an overall fission effect by increasing the ratio of mitochondrial fission over fusion proteins, leading to excessive dysfunctional fragmented mitochondria. Knocking down endogenous Pink1 produces similar effects. In contrast, overexpressing human wild type PINK1 produces a pro-fusion effect by increasing the ratio of mitochondrial fusion/fission proteins without resulting in functionally compromised mitochondria. Parkin knockdown blocks the imbalance in fission/fusion proteins. Furthermore, overexpressing parkin and ubiquitin increases degradation of the mitochondrial fission hFis1 protein, suggesting PINK1 and parkin maintain proper mitochondrial function and integrity via the fission/fusion machinery. Through genetic manipulations and treatment with the small molecule mitochondrial division inhibitor (mdivi-1), which inhibits DLP1/Drp1, both structural and functional mitochondrial defects induced by mutant PINK1 were attenuated, highlighting a potential novel therapeutic avenue for Parkinson disease.
authors.affiliation: Department of Neurology, University of Rochester School of Medicine, Rochester, New York 14642, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.forename: Xiangna
authors.initials: X
authors.lastname: Tang
authors.forename: Whitney V
authors.initials: WV
authors.lastname: Christian
authors.forename: Yisang
authors.initials: Y
authors.lastname: Yoon
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
mesh_terms: D000818:Animals; D034281:Dynamins / Q000378:metabolism; D020558:GTP Phosphohydrolases; D005821:Genetic Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D034281:Dynamins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D052999:Quinazolinones; D034741:RNA, Small Interfering; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C476525:FIS1 protein, human; C111567:parkin protein; C470018:MFN2 protein, human; C519851:Dnm1l protein, rat