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

Pedro M. Quirós, Miguel A. Prado, Nicola Zamboni, Davide D'Amico, Robert Williams, Daniel Finley, Steven P. Gygi, Johan Auwerx

Research output: Contribution to journalArticle

91 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2027-2045
Number of pages19
JournalJournal of Cell Biology
Volume216
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Activating Transcription Factor 4
Mammals
Mitochondrial Diseases
Mitochondrial Proteins
Unfolded Protein Response
Gene Expression
Ribosomal Proteins
Quantitative Trait Loci
Genes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. / Quirós, Pedro M.; Prado, Miguel A.; Zamboni, Nicola; D'Amico, Davide; Williams, Robert; Finley, Daniel; Gygi, Steven P.; Auwerx, Johan.

In: Journal of Cell Biology, Vol. 216, No. 7, 01.07.2017, p. 2027-2045.

Research output: Contribution to journalArticle

Quirós, PM, Prado, MA, Zamboni, N, D'Amico, D, Williams, R, Finley, D, Gygi, SP & Auwerx, J 2017, 'Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals', Journal of Cell Biology, vol. 216, no. 7, pp. 2027-2045. https://doi.org/10.1083/jcb.201702058
Quirós, Pedro M. ; Prado, Miguel A. ; Zamboni, Nicola ; D'Amico, Davide ; Williams, Robert ; Finley, Daniel ; Gygi, Steven P. ; Auwerx, Johan. / Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. In: Journal of Cell Biology. 2017 ; Vol. 216, No. 7. pp. 2027-2045.
@article{03c9d480c0d84e95a37f2c259554a488,
title = "Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals",
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.",
author = "Quir{\'o}s, {Pedro M.} and Prado, {Miguel A.} and Nicola Zamboni and Davide D'Amico and Robert Williams and Daniel Finley and Gygi, {Steven P.} and Johan Auwerx",
year = "2017",
month = "7",
day = "1",
doi = "10.1083/jcb.201702058",
language = "English (US)",
volume = "216",
pages = "2027--2045",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

AU - Quirós, Pedro M.

AU - Prado, Miguel A.

AU - Zamboni, Nicola

AU - D'Amico, Davide

AU - Williams, Robert

AU - Finley, Daniel

AU - Gygi, Steven P.

AU - Auwerx, Johan

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85021857064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021857064&partnerID=8YFLogxK

U2 - 10.1083/jcb.201702058

DO - 10.1083/jcb.201702058

M3 - Article

C2 - 28566324

AN - SCOPUS:85021857064

VL - 216

SP - 2027

EP - 2045

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 7

ER -