PINK1-mediated phosphorylation of Miro inhibits synaptic growth and protects dopaminergic neurons in Drosophila.
Mutations in the mitochondrial Ser/Thr kinase PINK1 cause Parkinson's disease. One of the substrates of PINK1 is the outer mitochondrial membrane protein Miro, which regulates mitochondrial transport. In this study, we uncovered novel physiological functions of PINK1-mediated phosphorylation of Miro, using Drosophila as a model. We replaced endogenous Drosophila Miro (DMiro) with transgenically expressed wildtype, or mutant DMiro predicted to resist PINK1-mediated phosphorylation. We found that the expression of phospho-resistant DMiro in a DMiro null mutant background phenocopied a subset of phenotypes of PINK1 null. Specifically, phospho-resistant DMiro increased mitochondrial movement and synaptic growth at larval neuromuscular junctions, and decreased the number of dopaminergic neurons in adult brains. Therefore, PINK1 may inhibit synaptic growth and protect dopaminergic neurons by phosphorylating DMiro. Furthermore, muscle degeneration, swollen mitochondria and locomotor defects found in PINK1 null flies were not observed in phospho-resistant DMiro flies. Thus, our study established an in vivo platform to define functional consequences of PINK1-mediated phosphorylation of its substrates.
Department of Neurosurgery, Stanford University School of Medicine, Stanford. CA94304.
Pei-I
PI
Tsai
1] Department of Neurosurgery, Stanford University School of Medicine, Stanford. CA94304 [2] Neurosciences Program, Stanford University, Stanford. CA94304.
Meredith M
MM
Course
Department of Neurosurgery, Stanford University School of Medicine, Stanford. CA94304.
Jonathan R
JR
Lovas
Department of Neurosurgery, Stanford University School of Medicine, Stanford. CA94304.
Chung-Han
CH
Hsieh
Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson. AZ85721.
Milos
M
Babic
1] Department of Neuroscience, University of Arizona, Tucson. AZ85721 [2] Department of Molecular and Cellular Biology, University of Arizona, TucsonAZ85721.
Konrad E
KE
Zinsmaier
Department of Neurosurgery, Stanford University School of Medicine, Stanford. CA94304.
Xinnan
X
Wang
D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007814:Larva / Q000235:genetics / Q000378:metabolism; D008124:Locomotion / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C504427:Miro protein, Drosophila