PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane
Copyright policy )PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane
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.
- University of California System United States
- Department of Pathology Stanford University School of Medicine United States
- Stanford University United States
- Goethe University Frankfurt Germany
- Stanford University School of Medicine United States
Physiology, Ubiquitin-Protein Ligases, Neurodegenerative, Medical Biochemistry and Metabolomics, Protein Serine-Threonine Kinases, Small Interfering, Rats, Sprague-Dawley, Endocrinology & Metabolism, Genetics, Animals, Drosophila Proteins, Guanine Nucleotide Exchange Factors, Humans, RNA, Small Interfering, Molecular Biology, Parkinson's Disease, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Neurosciences, Ubiquitination, Nuclear Proteins, RNA-Binding Proteins, Cell Biology, Brain Disorders, Mitochondria, Rats, DNA-Binding Proteins, Drosophila melanogaster, HEK293 Cells, Electron Transport Chain Complex Proteins, Protein Biosynthesis, Neurological, Mitochondrial Membranes, RNA, Generic health relevance, Sprague-Dawley, Biochemistry and Cell Biology, Lipid Peroxidation
Physiology, Ubiquitin-Protein Ligases, Neurodegenerative, Medical Biochemistry and Metabolomics, Protein Serine-Threonine Kinases, Small Interfering, Rats, Sprague-Dawley, Endocrinology & Metabolism, Genetics, Animals, Drosophila Proteins, Guanine Nucleotide Exchange Factors, Humans, RNA, Small Interfering, Molecular Biology, Parkinson's Disease, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Neurosciences, Ubiquitination, Nuclear Proteins, RNA-Binding Proteins, Cell Biology, Brain Disorders, Mitochondria, Rats, DNA-Binding Proteins, Drosophila melanogaster, HEK293 Cells, Electron Transport Chain Complex Proteins, Protein Biosynthesis, Neurological, Mitochondrial Membranes, RNA, Generic health relevance, Sprague-Dawley, Biochemistry and Cell Biology, Lipid Peroxidation
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