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 FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans

Genetics ◽  
2019 ◽  
Vol 214 (2) ◽  
pp. 409-418 ◽  
Author(s):  
Sungjin Kim ◽  
Derek Sieburth
Keyword(s):  
Caenorhabditis Elegans ◽  
Unfolded Protein Response ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Link Type ◽  
Link Functions ◽  
Evolutionarily Conserved ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.

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 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 A New Vision of Mitochondrial Unfolded Protein Response to the Sirtuin Family

2020 ◽  
Vol 18 (7) ◽  
pp. 613-623 ◽  
Author(s):  
Huidan Weng ◽  
Yihong Ma ◽  
Lina Chen ◽  
Guoen Cai ◽  
Zhiting Chen ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Tumor Development ◽  
Mitochondrial Damage ◽  
Protective Response ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
New Vision ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondrial damage is involved in many pathophysiological processes, such as tumor development, metabolism, and neurodegenerative diseases. The mitochondrial unfolded protein response (mtUPR) is the first stress-protective response initiated by mitochondrial damage, and it repairs or clears misfolded proteins to alleviate this damage. Studies have confirmed that the sirtuin family is essential for the mitochondrial stress response; in particular, SIRT1, SIRT3, and SIRT7 participate in the mtUPR in different axes. This article summarizes the associations of sirtuins with the mtUPR as well as specific molecular targets related to the mtUPR in different disease models, which will provide new inspiration for studies on mitochondrial stress, mitochondrial function protection, and mitochondria-related diseases, such as neurodegenerative diseases.

scholarly journals Role of the mitochondrial stress response in human cancer progression

2020 ◽  
Vol 245 (10) ◽  
pp. 861-878 ◽  
Author(s):  
Sheng-Fan Wang ◽  
Shiuan Chen ◽  
Ling-Ming Tseng ◽  
Hsin-Chen Lee
Keyword(s):  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Cancer Progression ◽  
Stress Responses ◽  
Retrograde Signaling ◽  
Cancer Targeting ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondria are important organelles that are responsible for cellular energy metabolism, cellular redox/calcium homeostasis, and cell death regulation in mammalian cells. Mitochondrial dysfunction is involved in various diseases, such as neurodegenerative diseases, cardiovascular diseases, immune disorders, and cancer. Defective mitochondria and metabolism remodeling are common characteristics in cancer cells. Several factors, such as mitochondrial DNA copy number changes, mitochondrial DNA mutations, mitochondrial enzyme defects, and mitochondrial dynamic changes, may contribute to mitochondrial dysfunction in cancer cells. Some lines of evidence have shown that mitochondrial dysfunction may promote cancer progression. Here, several mitochondrial stress responses, including the mitochondrial unfolded protein response and the integrated stress response, and several mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and others) are reviewed; these pathways and molecules are considered to act as retrograde signaling regulators in the development and progression of cancer. Targeting these components of the mitochondrial stress response may be an important strategy for cancer treatment. Impact statement Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.

scholarly journals FSHR-1/GPCR activates the mitochondrial unfolded protein response in Caenorhabditis elegans

2019 ◽  
Author(s):  
Sungjin Kim ◽  
Derek Sieburth
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Stress ◽  
C Elegans ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Evolutionarily Conserved ◽  
Genetic Deficiency ◽  
Protein Response ◽  
G Protein Coupled ◽  
Mitochondrial Unfolded Protein Response

AbstractThe mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In C. elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues is not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein coupled receptor (GPCR), FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell non-autonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.

scholarly journals Folding Mitochondrial-Mediated Cytosolic Proteostasis Into the Mitochondrial Unfolded Protein Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Edmund Charles Jenkins ◽  
Mrittika Chattopadhyay ◽  
Doris Germain
Keyword(s):  
Unfolded Protein Response ◽  
Cross Talk ◽  
Model Organisms ◽  
Multiple Model ◽  
Musical Piece ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
The Cross ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Several studies reported that mitochondrial stress induces cytosolic proteostasis. How mitochondrial stress activates proteostasis in the cytosol remains unclear. However, the cross-talk between the mitochondria and cytosolic proteostasis has far reaching implications for treatment of proteopathies including neurodegenerative diseases. This possibility appears within reach since selected drugs have begun to emerge as being able to stimulate mitochondrial-mediated cytosolic proteostasis. In this review, we focus on studies describing how mitochondrial stress activates proteostasis in the cytosol across multiple model organisms. A model is proposed linking mitochondrial-mediated regulation of cytosolic translation, folding capacity, ubiquitination, and proteasome degradation and autophagy as a multi layered control of cytosolic proteostasis that overlaps with the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). By analogy to the conductor in an orchestra managing multiple instrumental sections into a dynamically integrated musical piece, the cross-talk between these signaling cascades places the mitochondria as a major conductor of cellular integrity.

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