Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Animals, Genetically Modified
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Brain / metabolism*
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Brain / pathology
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Disease Models, Animal
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Dopaminergic Neurons / metabolism*
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Dopaminergic Neurons / pathology
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Drosophila Proteins / deficiency
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism*
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Gene Expression Regulation
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Humans
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Larva / genetics
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Larva / metabolism
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Locomotion / genetics
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Diseases / genetics
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Mitochondrial Diseases / metabolism
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Mitochondrial Diseases / pathology
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Muscles / metabolism
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Muscles / pathology
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Mutation
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Neuromuscular Junction / genetics
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Neuromuscular Junction / metabolism*
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Neuromuscular Junction / pathology
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Parkinson Disease / genetics
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Phenotype
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Phosphorylation
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Signal Transduction
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Synapses / metabolism
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Synapses / pathology
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / metabolism*
Substances
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Drosophila Proteins
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PINK1 protein, Drosophila
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Protein Serine-Threonine Kinases
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Miro protein, Drosophila
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rho GTP-Binding Proteins
Supplementary concepts
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Parkinson Disease, Mitochondrial