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

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,…

• NS
  National Science Foundation
• EM
  European Molecular Biology Organization

  Award: ALTF 480–2014
• ÉP
  École Polytechnique Fédérale de Lausanne
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  Awards: 140780, 31003A-140780, 31003A
• KS
  Krebsliga Schweiz

  Award: KFS-3082-02-2013
• AI
  Associazione Italiana per la Ricerca sul Cancro
• NI
  National Institutes of Health

  Awards: R01AG043930, GM67945, R01GM095526