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

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Yasmine J. Liu ◽  
Rebecca L. McIntyre ◽  
Georges E. Janssens ◽  
Evan G. Williams ◽  
Jiayi Lan ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Network ◽  
Mitochondrial Translation ◽  
C Elegans ◽  
Form And Function ◽  
Unfolded Protein ◽  
Lysosome Biogenesis ◽  
And Function ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates 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 crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.

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.

scholarly journals At the heart of mitochondrial quality control: many roads to the top

2021 ◽  
Author(s):  
Roberta A. Gottlieb ◽  
Honit Piplani ◽  
Jon Sin ◽  
Savannah Sawaged ◽  
Syed M. Hamid ◽  
...  
Keyword(s):  
Quality Control ◽  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Unfolded Protein ◽  
Selective Elimination ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial quality control depends upon selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistribution of mitochondrial components across the network by fusion, and segregation of damaged mitochondria by fission prior to mitophagy. In this review, we focus on mitochondrial dynamics (fusion/fission), mitophagy, and other mechanisms supporting mitochondrial quality control including maintenance of mtDNA and the mitochondrial unfolded protein response, particularly in the context of the heart.

scholarly journals Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

2019 ◽  
Vol 5 (4) ◽  
pp. eaaw0025 ◽  
Author(s):  
Milos S. Simic ◽  
Erica A. Moehle ◽  
Robert T. Schinzel ◽  
Franziska K. Lorbeer ◽  
Jonathan J. Halloran ◽  
...  
Keyword(s):  
Cellular Reprogramming ◽  
Epigenetic Landscape ◽  
Form And Function ◽  
Unfolded Protein ◽  
Transient Activation ◽  
Reprogramming Efficiency ◽  
Low Efficiency ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.

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 Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

2018 ◽  
Author(s):  
Milos S. Simic ◽  
Erica Moehle ◽  
Robert T. Schinzel ◽  
Franziska Lorbeer ◽  
Damien Jullié ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Cellular Reprogramming ◽  
Pluripotent State ◽  
Form And Function ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Transient Activation ◽  
Low Efficiency ◽  
And Function ◽  
Protein Response

AbstractSomatic cells can be reprogrammed into pluripotent stem cells by the forced expression of the OCT4, SOX2, KLF4 and c-MYC transcription factors. This process requires the reshaping of not only epigenetic landscapes, but the global remodeling of cell identity, structure, and function including such basic processes of metabolism and organelle form and function. Cellular reprogramming is a stochastic process with only a marginally measureable fraction of cells successfully crossing these, and many other, cellular epitomes to acquire the fully pluripotent state. We hypothesize that this variation is due, in part, by variable regulation of the proteostasis network and its influence upon the protein folding environment within cells and their organelles upon the remodeling process. We find that the endoplasmic reticulum unfolded protein response (UPRER), the heat-shock response (HSR) and the mitochondrial unfolded protein response (UPRmt), which monitor and ensure the quality of the proteome of, respectively, the ER, the cytosol and the mitochondria during stress, are activated during cellular reprogramming. Particularly, we find that the UPRER is essential for reprograming, and ectopic, transient activation of the UPRER, either genetically or pharmacologically, enhances the success of cells to reach a pluripotent state. Finally, and most revealing, we find that stochastic activation of the UPRER can predict the reprogramming efficiency of naïve cells. The results of these experiments indicate that the low efficiency and stochasticity of cellular reprogramming is partly the result of the inability to initiate a proper ER stress response for remodeling of the ER and its proteome during the reprogramming process. The results reported here display only one aspect of the proteostasis network and suggest that proper regulation of many more components of this network might be essential to acquire the pluripotent state.

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 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 Structure and Function of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Yi Luan ◽  
Ying Luan ◽  
Rui-Xia Yuan ◽  
Qi Feng ◽  
Xing Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Vascular Endothelial Cells ◽  
Mitochondrial Dynamics ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Associated Proteins ◽  
Apoptosis And Inflammation ◽  
And Function ◽  
Protein Response

Abnormal function of suborganelles such as mitochondria and endoplasmic reticulum often leads to abnormal function of cardiomyocytes or vascular endothelial cells and cardiovascular disease (CVD). Mitochondria-associated membrane (MAM) is involved in several important cellular functions. Increasing evidence shows that MAM is involved in the pathogenesis of CVD. MAM mediates multiple cellular processes, including calcium homeostasis regulation, lipid metabolism, unfolded protein response, ROS, mitochondrial dynamics, autophagy, apoptosis, and inflammation, which are key risk factors for CVD. In this review, we discuss the structure of MAM and MAM-associated proteins, their role in CVD progression, and the potential use of MAM as the therapeutic targets for CVD treatment.

Sign in / Sign up

Export Citation Format

Share Document