Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans

Cell Metab. 2015 Mar 3;21(3):428-42. doi: 10.1016/j.cmet.2015.01.019.

Abstract

Transfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms(2)) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms(2) modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms(2) modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms(2) modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mitochondrial Diseases / genetics*
  • Muscular Diseases / genetics*
  • Nerve Tissue Proteins / genetics*
  • Oxidative Stress / genetics
  • Protein Biosynthesis / genetics*
  • RNA Processing, Post-Transcriptional / genetics
  • RNA, Transfer / genetics*

Substances

  • CDK5RAP1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • RNA, Transfer