Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme

Nat Cell Biol. 2019 Apr;21(4):442-451. doi: 10.1038/s41556-019-0294-5. Epub 2019 Mar 18.


The cytosolic accumulation of mitochondrial precursors is hazardous to cellular fitness and is associated with a number of diseases. However, it is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive. Here, we show that cells rapidly launch a global transcriptional programme to restore cellular proteostasis after induction of a 'clogger' protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodelling is a combination of a 'wideband' core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the oxidative phosphorylation components, mediated by an inactivation of the HAP complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytosol / enzymology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Fungal*
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Response
  • Mitochondrial Proteins / metabolism*
  • Oxidative Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Biosynthesis
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / biosynthesis
  • Saccharomyces cerevisiae Proteins / metabolism
  • Stress, Physiological / genetics*
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Ubiquitin / metabolism


  • DNA-Binding Proteins
  • HSF1 protein, S cerevisiae
  • Heat-Shock Proteins
  • Mitochondrial Proteins
  • RPN4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Ubiquitin
  • Proteasome Endopeptidase Complex