scholarly journals Sensing, signaling and surviving mitochondrial stress

2021 ◽  
Author(s):  
Eva-Maria Eckl ◽  
Olga Ziegemann ◽  
Luisa Krumwiede ◽  
Evelyn Fessler ◽  
Lucas T. Jae
Keyword(s):  
Mitochondrial Function ◽  
Building Blocks ◽  
Mitochondrial Network ◽  
Mitochondrial Proteome ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
Control Factors ◽  
Different Types ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.

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 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 UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import

2020 ◽  
Author(s):  
Tomer Shpilka ◽  
YunGuang Du ◽  
Qiyun Yang ◽  
Andrew Melber ◽  
Nandhitha U. Naresh ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Protein Import ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Import ◽  
Network Expansion ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractAs organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS)1. Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS2 in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPRmt activity throughout development due to increased accumulation within mitochondria. The insulin-like signaling-TORC13 and AMPK pathways affected UPRmt activation4,5 in a manner that correlated with protein synthesis. Manipulation to increase protein synthesis caused UPRmt activation. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial accumulation of ATFS-1. However, ATFS-1 with a dysfunctional MTS6 constitutively increased UPRmt activity independent of TORC1 function. Lastly, expression of a single protein with a strong MTS, was sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation. Mitochondrial network expansion is attenuated once ATFS-1 can be imported.

scholarly journals Mild impairment of mitochondrial function increases longevity and pathogen resistance through ATFS-1-driven activation of p38-regulated innate immunity

2021 ◽  
Author(s):  
Juliane Campos ◽  
Ziyun Wu ◽  
Paige D Rudich ◽  
Sonja Soo ◽  
Meeta Mistry ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mitochondrial Function ◽  
Innate Immune ◽  
Unfolded Protein ◽  
Innate Immune Signaling ◽  
Immune Signaling Pathway ◽  
Mild Impairment ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response ◽  
Innate Immune Signaling Pathway

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain resulted in upregulation of genes involved in innate immunity, which we found to be dependent on not only the canonical p38-mediated innate immune signaling pathway but also on the mitochondrial unfolded protein response. Both of these pathways are absolutely required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitochondrial unfolded protein response can act on the same innate immunity genes to promote resistance to bacterial pathogens, and that input from the mitochondria can extend longevity by signaling through these two pathways. Combined, this indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.

scholarly journals Mitochondrial unfolded protein response gene CLPP changes mitochondrial dynamics and affects mitochondrial function

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7209 ◽  
Author(s):  
GuiJun Wu ◽  
Qing Xiong ◽  
XiaoJun Wei ◽  
Ye Wang ◽  
XueMei Hu ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Function ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
High Fat ◽  
Response Gene ◽  
Min6 Cells ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondrial dynamics is associated with mitochondrial function, which is associated with diabetes. Although an important indicator of the mitochondrial unfolded protein response, to the best of our knowledge, CLPP and its effects on mitochondrial dynamics in islet cells have not been studied to date. We analyzed the effects of CLPP on mitochondrial dynamics and mitochondrial function in the mice islet β-cell line Min6 under high glucose and high fat conditions. Min6 cells were assigned to: Normal, HG, HG+NC, HG+siCLPP, HF, HF+NC and HF+ siCLPP groups. High glucose and high fat can promote the mRNA and protein expression of CLPP in mitochondria. The increase of mitochondrial fission, the decrese of mitochondrial fusion, and the damage of mintocondrial ultrastructure were significant in the siCLPP cell groups as compared to no-siCLPP treated groups. Meanwhile, mitochondrial functions of MIN6 cells treated with siCLPP were impaired, such as ATP decreased, ROS increased, mitochondrial membrane potential decreased. In addition, cell insulin secretion decreased and cell apoptosis rate increased in siCLPP groups. These results revealed that mitochondrial unfolded protein response geneCLPP alleviated high glucose and high fat-induced mitochondrial dynamics imbalance and mitochondrial dysfunction.

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.

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