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 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 Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Li-Wa Shao ◽  
Qi Peng ◽  
Mingyue Dong ◽  
Kaiyu Gao ◽  
Yumei Li ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mammalian Cells ◽  
Metabolic Reprogramming ◽  
Mitochondrial Stress ◽  
C Elegans ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Evolutionarily Conserved ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Abstract The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.

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 A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

Aging Cell ◽  
2018 ◽  
Vol 17 (6) ◽  
pp. e12830 ◽  
Author(s):  
Mehrnaz Shamalnasab ◽  
Simon-Pierre Gravel ◽  
Julie St-Pierre ◽  
Lionel Breton ◽  
Sibylle Jäger ◽  
...  
Keyword(s):  
Salicylic Acid ◽  
Caenorhabditis Elegans ◽  
Unfolded Protein Response ◽  
Acid Derivative ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

scholarly journals Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Christopher F. Bennett ◽  
Helen Vander Wende ◽  
Marissa Simko ◽  
Shannon Klum ◽  
Sarah Barfield ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

scholarly journals The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0159989 ◽  
Author(s):  
Salvador Peña ◽  
Teresa Sherman ◽  
Paul S. Brookes ◽  
Keith Nehrke
Keyword(s):  
Caenorhabditis Elegans ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

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 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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