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 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 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 A conserved role of CBP/p300 in mitochondrial stress response and longevity

2020 ◽  
Author(s):  
Terytty Yang Li ◽  
Maroun Bou Sleiman ◽  
Hao Li ◽  
Arwen W. Gao ◽  
Adrienne Mottis ◽  
...  
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Amyloid Β ◽  
Human Populations ◽  
Histone Demethylases ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Evolutionarily Conserved ◽  
Protein Response

Abstract Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

scholarly journals SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate immunity and lifespan extension

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kaiyu Gao ◽  
Yi Li ◽  
Shumei Hu ◽  
Ying Liu
Keyword(s):  
Immune Response ◽  
Transcriptional Response ◽  
Lifespan Extension ◽  
Transcriptional Program ◽  
Post Translational Modification ◽  
Mitochondrial Stress ◽  
C Elegans ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Animals respond to mitochondrial stress with the induction of mitochondrial unfolded protein response (UPRmt). A cascade of events occur upon UPRmt activation, ultimately triggering a transcriptional response governed by two transcription factors: DVE-1 and ATFS-1. Here we identify SUMO-specific peptidase ULP-4 as a positive regulator of C. elegans UPRmt to control SUMOylation status of DVE-1 and ATFS-1. SUMOylation affects these two axes in the transcriptional program of UPRmt with distinct mechanisms: change of DVE-1 subcellular localization vs. change of ATFS-1 stability and activity. Our findings reveal a post-translational modification that promotes immune response and lifespan extension during mitochondrial stress.

scholarly journals ClpP Mediates Activation of a Mitochondrial Unfolded Protein Response in C. elegans

2007 ◽  
Vol 13 (4) ◽  
pp. 467-480 ◽  
Author(s):  
Cole M. Haynes ◽  
Kseniya Petrova ◽  
Cristina Benedetti ◽  
Yun Yang ◽  
David Ron
Keyword(s):  
Unfolded Protein Response ◽  
C Elegans ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

scholarly journals Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

2019 ◽  
Author(s):  
Blanca Hernando-Rodríguez ◽  
Mercedes M. Pérez-Jiménez ◽  
María Jesús Rodríguez-Palero ◽  
Antoni Pla ◽  
Manuel David Martínez-Bueno ◽  
...  
Keyword(s):  
Membrane Lipid ◽  
Wild Type ◽  
Autophagy Flux ◽  
Yolk Formation ◽  
Membrane Lipid Composition ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Contact Sites ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar effect on lifespan. While PHB depletion shortens lifespan of wild type animals, it enhances longevity of a plethora of metabolically compromised mutants, including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, we show that sgk-1 mutants have impaired mitochondrial homeostasis, lipogenesis, yolk formation and autophagy flux due to alterations in membrane lipid and sterol homeostasis. Remarkably, all these features are suppressed by PHB depletion. Lifespan analysis shows that autophagy and the mitochondrial unfolded protein response (UPRmt), but not mitophagy, are required for the enhanced longevity caused by PHB depletion in sgk-1 mutants. We hypothesize that UPRmt induction upon PHB depletion extends lifespan of sgk-1 mutants through autophagy. Our results strongly suggest that PHB depletion suppresses the autophagy defects of sgk-1 mutants by altering membrane lipid composition at ER-mitochondria contact sites, where TORC2 localizes.

scholarly journals Induction of RNA interference by C. elegans mitochondrial dysfunction via the DRH-1/RIG-I homologue RNA helicase and the EOL-1/RNA decapping enzyme

2020 ◽  
Author(s):  
Kai Mao ◽  
Peter Breen ◽  
Gary Ruvkun
Keyword(s):  
Rna Interference ◽  
Mitochondrial Dysfunction ◽  
C Elegans ◽  
Antiviral Responses ◽  
Unfolded Protein ◽  
Decapping Enzyme ◽  
Protein Response ◽  
Rna Decapping ◽  
Mitochondrial Unfolded Protein Response ◽  
Transcriptional Induction

AbstractRNA interference (RNAi) is an antiviral pathway common to many eukaryotes that detects and cleaves foreign nucleic acids. In mammals, mitochondrially localized proteins such as MAVS, RIG-I, and MDA5 mediate antiviral responses. Here, we report that mitochondrial dysfunction in Caenorhabditis elegans activates RNAi-directed silencing via induction of a pathway homologous to the mammalian RIG-I helicase viral response pathway. The induction of RNAi also requires the conserved RNA decapping enzyme EOL-1/DXO. The transcriptional induction of eol-1 requires DRH-1 as well as the mitochondrial unfolded protein response (UPRmt). Upon mitochondrial dysfunction, EOL-1 is concentrated into foci that depend on the transcription of mitochondrial RNAs that may form dsRNA, as has been observed in mammalian antiviral responses. The enhanced RNAi triggered by mitochondrial dysfunction contributes to the increase in longevity that is induced by mitochondrial dysfunction.

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 Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

2019 ◽  
Author(s):  
Yasmine J. Liu ◽  
Rebecca L. McIntyre ◽  
Georges E. Janssens ◽  
Evan G. Williams ◽  
Jiayi Lan ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Mitochondrial Network ◽  
Mitochondrial Translation ◽  
C Elegans ◽  
Form And Function ◽  
Unfolded Protein ◽  
Lysosome Biogenesis ◽  
And Function ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

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