Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

J Cell Biol. 2017 Jul 3;216(7):2027-2045. doi: 10.1083/jcb.201702058. Epub 2017 May 31.


Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans-expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Computational Biology
  • Disease Models, Animal
  • Endopeptidase Clp / genetics
  • Endopeptidase Clp / metabolism
  • Energy Metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Genomics / methods*
  • HeLa Cells
  • High-Temperature Requirement A Serine Peptidase 2
  • Humans
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Phenotype
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Interaction Maps
  • Proteolysis
  • Proteome
  • Proteomics / methods*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Signal Transduction
  • Stress, Physiological*
  • Time Factors
  • Transcriptome
  • Transfection


  • ATF4 protein, human
  • Atf4 protein, mouse
  • Mitochondrial Proteins
  • Proteome
  • Ribosomal Proteins
  • Activating Transcription Factor 4
  • Serine Endopeptidases
  • High-Temperature Requirement A Serine Peptidase 2
  • CLPP protein, mouse
  • Endopeptidase Clp
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease