PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane

Cell Metab. 2015 Jan 6;21(1):95-108. doi: 10.1016/j.cmet.2014.12.007.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism
  • Electron Transport Chain Complex Proteins / genetics
  • Electron Transport Chain Complex Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism
  • Humans
  • Lipid Peroxidation
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Electron Transport Chain Complex Proteins
  • Glo protein, Drosophila
  • Guanine Nucleotide Exchange Factors
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • Nuclear Proteins
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Tom protein, Drosophila
  • pum protein, Drosophila
  • tim protein, Drosophila
  • RCC1 protein, Drosophila
  • Ubiquitin-Protein Ligases
  • PINK1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • park protein, Drosophila