Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response

Mitochondrion ◽  
2015 ◽  
Vol 21 ◽  
pp. 58-68 ◽  
Author(s):  
Sebastien Michel ◽  
Morgane Canonne ◽  
Thierry Arnould ◽  
Patricia Renard
Keyword(s):  
Stress Response ◽  
Mitochondrial Genome ◽  
Cell Signaling ◽  
Unfolded Protein Response ◽  
Integrated Stress Response ◽  
Unfolded Protein ◽  
Genome Expression ◽  
A Cell ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

scholarly journals Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Katsuhiko Sasaki ◽  
Takeshi Uchiumi ◽  
Takahiro Toshima ◽  
Mikako Yagi ◽  
Yura Do ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Stress Response ◽  
Unfolded Protein Response ◽  
Integrated Stress Response ◽  
Mitochondrial Translation ◽  
Translation Inhibition ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Abstract Mitochondrial–nuclear communication, known as retrograde signaling, is important for regulating nuclear gene expression in response to mitochondrial dysfunction. Previously, we have found that p32/C1qbp-deficient mice, which have a mitochondrial translation defect, show endoplasmic reticulum (ER) stress response and integrated stress response (ISR) gene expression in the heart and brain. However, the mechanism by which mitochondrial translation inhibition elicits these responses is not clear. Among the transcription factors that respond to mitochondrial stress, activating transcription factor 4 (ATF4) is a key transcription factor in the ISR. Herein, chloramphenicol (CAP), which inhibits mitochondrial DNA (mtDNA)-encoded protein expression, induced eukaryotic initiation factor 2 α subunit (eIF2α) phosphorylation and ATF4 induction, leading to ISR gene expression. However, the expression of the mitochondrial unfolded protein response (mtUPR) genes, which has been shown in Caenorhabditis elegans, was not induced. Short hairpin RNA-based knockdown of ATF4 markedly inhibited the CAP-induced ISR gene expression. We also observed by ChIP analysis that induced ATF4 bound to the promoter region of several ISR genes, suggesting that mitochondrial translation inhibition induces ISR gene expression through ATF4 activation. In the present study, we showed that mitochondrial translation inhibition induced the ISR through ATF4 activation rather than the mtUPR.

scholarly journals Homolog of ELAC2 is a central regulator of the mitochondrial unfolded protein response

2021 ◽  
Author(s):  
James P Held ◽  
Benjamin R Saunders ◽  
Claudia V Pereria ◽  
Maulik R Patel
Keyword(s):  
Transcription Factors ◽  
Stress Response ◽  
Unfolded Protein Response ◽  
Negative Regulation ◽  
Mitochondrial Stress ◽  
Trna Processing ◽  
Unfolded Protein ◽  
Necessary And Sufficient ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We unexpectedly discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is central to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.

scholarly journals Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors

2021 ◽  
Vol 4 (12) ◽  
pp. e202101182
Author(s):  
Sonja K Soo ◽  
Annika Traa ◽  
Paige D Rudich ◽  
Meeta Mistry ◽  
Jeremy M Van Raamsdonk
Keyword(s):  
Stress Response ◽  
Unfolded Protein Response ◽  
Vital Role ◽  
Antioxidant Genes ◽  
Multiple Stress ◽  
Constitutive Activation ◽  
Unfolded Protein ◽  
Stress Response Pathway ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to mitochondria insults through transcriptional changes, mediated by the transcription factor ATFS-1/ATF-5, which acts to restore mitochondrial homeostasis. In this work, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause up-regulation of genes involved in multiple stress response pathways including the DAF-16–mediated stress response pathway, the cytosolic unfolded protein response, the endoplasmic reticulum unfolded protein response, the SKN-1–mediated oxidative stress response pathway, the HIF-1-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, whereas disruption of atfs-1 decreases stress resistance. Although ATFS-1–dependent genes are up-regulated in multiple long-lived mutants, constitutive activation of ATFS-1 decreases lifespan in wild-type animals. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stressors through its ability to activate multiple stress response pathways but that chronic ATFS-1 activation is detrimental for longevity.

scholarly journals Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response

Nature ◽  
2016 ◽  
Vol 533 (7603) ◽  
pp. 416-419 ◽  
Author(s):  
Yi-Fan Lin ◽  
Anna M. Schulz ◽  
Mark W. Pellegrino ◽  
Yun Lu ◽  
Shai Shaham ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

scholarly journals Mitochondrial unfolded protein response transcription factor ATFS-1 increases resistance to exogenous stressors through upregulation of multiple stress response pathways

2021 ◽  
Author(s):  
Sonja K. Soo ◽  
Annika Traa ◽  
Meeta Mistry ◽  
Jeremy M. Van Raamsdonk
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Stress Response ◽  
Unfolded Protein Response ◽  
Multiple Stress ◽  
Constitutive Activation ◽  
Unfolded Protein ◽  
Stress Response Pathway ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractThe mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to various insults to the mitochondria through transcriptional changes that restore mitochondrial homeostasis in order to facilitate cell survival. Gene expression changes resulting from the activation of the mitoUPR are mediated by the transcription factor ATFS-1/ATF-5. To further define the mechanisms through which the mitoUPR protects the cell during mitochondrial dysfunction, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause upregulation of genes involved in multiple stress response pathways, including the DAF-16-mediated stress response pathway, the SKN-1-mediated oxidative stress response pathway, the HIF-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Moreover, ATFS-1 is required for the upregulation of stress response genes after exposure to exogenous stressors, especially oxidative stress and bacterial pathogens. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, while disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are upregulated in multiple long-lived mutants, constitutive activation of ATFS-1 in wild-type animals results in decreased lifespan. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stresses through its ability to activate multiple stress response pathways, but that chronic ATFS-1 activation is detrimental for longevity.

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