title: Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria.
abstract: Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sawada
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Wendou
authors.initials: W
authors.lastname: Yu
authors.forename: George
authors.initials: G
authors.lastname: Silverio
authors.forename: Philomena
authors.initials: P
authors.lastname: Alapatt
authors.forename: Ivan
authors.initials: I
authors.lastname: Millan
authors.forename: Alice
authors.initials: A
authors.lastname: Shen
authors.forename: William
authors.initials: W
authors.lastname: Saxton
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanao
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Imai
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001370:Axonal Transport / Q000235:genetics; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D061209:Proton Ionophores / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D029721:Drosophila Proteins; D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D061209:Proton Ionophores; D044767:Ubiquitin-Protein Ligases; D020741:rho GTP-Binding Proteins; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C504427:Miro protein, Drosophila; C487430:park protein, Drosophila