Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

EMBO J. 2019 Dec 16;38(24):e102155. doi: 10.15252/embj.2019102155. Epub 2019 Nov 13.


Translation fidelity is crucial for prokaryotes and eukaryotic nuclear-encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error-prone and hyper-accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian-specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.

Keywords: metabolism; mitochondria; mitochondrial ribosome; protein synthesis; stress response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Citric Acid Cycle / physiology
  • Escherichia coli / metabolism
  • Female
  • Metabolomics
  • Mice
  • Mice, Transgenic
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Organelle Biogenesis*
  • Protein Biosynthesis
  • Proteomics
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction*


  • Mitochondrial Proteins
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins