Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals
- PMID: 28566324
- PMCID: PMC5496626
- DOI: 10.1083/jcb.201702058
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.
© 2017 Quirós et al.
Figures
Similar articles
-
Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response.Biosci Rep. 2020 Nov 27;40(11):BSR20201289. doi: 10.1042/BSR20201289. Biosci Rep. 2020. PMID: 33165592 Free PMC article.
-
Intermedin/adrenomedullin 2 is a stress-inducible gene controlled by activating transcription factor 4.Gene. 2016 Sep 15;590(1):177-85. doi: 10.1016/j.gene.2016.06.037. Epub 2016 Jun 18. Gene. 2016. PMID: 27328454
-
The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals.Elife. 2021 Mar 1;10:e63326. doi: 10.7554/eLife.63326. Elife. 2021. PMID: 33646118 Free PMC article.
-
Mammalian mitochondrial ribosomal small subunit (MRPS) genes: A putative role in human disease.Gene. 2016 Sep 1;589(1):27-35. doi: 10.1016/j.gene.2016.05.008. Epub 2016 May 8. Gene. 2016. PMID: 27170550 Review.
-
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.Int J Mol Sci. 2023 Dec 13;24(24):17423. doi: 10.3390/ijms242417423. Int J Mol Sci. 2023. PMID: 38139251 Free PMC article. Review.
Cited by
-
Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.Nat Commun. 2024 Sep 27;15(1):8301. doi: 10.1038/s41467-024-52538-5. Nat Commun. 2024. PMID: 39333061 Free PMC article.
-
Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics.Oncotarget. 2024 Sep 17;15:614-633. doi: 10.18632/oncotarget.28637. Oncotarget. 2024. PMID: 39288289 Free PMC article.
-
Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.Research (Wash D C). 2024 Aug 30;7:0465. doi: 10.34133/research.0465. eCollection 2024. Research (Wash D C). 2024. PMID: 39221030 Free PMC article.
-
Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.iScience. 2024 Jul 19;27(8):110560. doi: 10.1016/j.isci.2024.110560. eCollection 2024 Aug 16. iScience. 2024. PMID: 39184436 Free PMC article.
-
OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.Mol Cell. 2024 Aug 22;84(16):3098-3114.e6. doi: 10.1016/j.molcel.2024.07.020. Epub 2024 Aug 13. Mol Cell. 2024. PMID: 39142278
References
-
- Adam J., Hatipoglu E., O’Flaherty L., Ternette N., Sahgal N., Lockstone H., Baban D., Nye E., Stamp G.W., Wolhuter K., et al. . 2011. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: Roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 20:524–537. 10.1016/j.ccr.2011.09.006 - DOI - PMC - PubMed
-
- Andreux P.A., Williams E.G., Koutnikova H., Houtkooper R.H., Champy M.F., Henry H., Schoonjans K., Williams R.W., and Auwerx J.. 2012. Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell. 150:1287–1299. 10.1016/j.cell.2012.08.012 - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous