title: PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane.
abstract: Mitochondria play essential roles in many aspects of biology, and their dysfunction has been linked to diverse diseases. Central to mitochondrial function is oxidative phosphorylation (OXPHOS), accomplished by respiratory chain complexes (RCCs) encoded by nuclear and mitochondrial genomes. How RCC biogenesis is regulated in metazoans is poorly understood. Here we show that Parkinson's disease (PD)-associated genes PINK1 and Parkin direct localized translation of certain nuclear-encoded RCC (nRCC) mRNAs. Translationally repressed nRCC mRNAs are localized in a PINK1/Tom20-dependent manner to mitochondrial outer membrane, where they are derepressed and activated by PINK1/Parkin through displacement of translation repressors, including Pumilio and Glorund/hnRNP-F, a Parkin substrate, and enhanced binding of activators such as eIF4G. Inhibiting the translation repressors rescued nRCC mRNA translation and neuromuscular-degeneration phenotypes of PINK1 mutant, whereas inhibiting eIF4G had opposite effects. Our results reveal previously unknown functions of PINK1/Parkin in RNA metabolism and suggest new approaches to mitochondrial restoration and disease intervention.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gehrke
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Experimental Neurology, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Programs in Biological Sciences and Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Experimental Neurology, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Programs in Biological Sciences and Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: su.guo@ucsf.edu.
authors.forename: Su
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: bingwei@stanford.edu.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D045222:Electron Transport Chain Complex Proteins; D020662:Guanine Nucleotide Exchange Factors; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D044767:Ubiquitin-Protein Ligases; C509827:Glo protein, Drosophila; C405938:Tom protein, Drosophila; C074333:pum protein, Drosophila; C096445:tim protein, Drosophila; C068687:RCC1 protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila