Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals
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Date
2017-07Type
- Journal Article
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Cited 365 times in
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Cited 382 times in
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Abstract
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. Show more
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https://doi.org/10.3929/ethz-b-000191490Publication status
publishedExternal links
Journal / series
The Journal of Cell BiologyVolume
Pages / Article No.
Publisher
Rockefeller University PressOrganisational unit
03713 - Sauer, Uwe / Sauer, Uwe
08839 - Zamboni, Nicola (Tit.-Prof.)
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Show all metadata
Citations
Cited 365 times in
Web of Science
Cited 382 times in
Scopus
ETH Bibliography
yes
Altmetrics