Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways

Wu, Ziyun; Senchuk, Megan M.; Dues, Dylan J.; Johnson, Benjamin K.; Cooper, Jason; Lew, Leira; Machiela, Emily; Schaar, Claire E.; DeJonge, Heather; Blackwell, T. Keith; Raamsdonk, Jeremy M. Van

doi:10.1186/s12915-018-0615-3

Cited by 87 publications

(142 citation statements)

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“…Having shown that mitochondrial morphology and function are disrupted in mitochondrial fission and fusion mutants, we investigated whether these deficits lead to an alteration of physiologic rates. Previous studies have demonstrated that mutations affecting the mitochondria often cause a slowing of physiologic rates 20,21,34‐36 . While wild‐type worms exhibit essentially no embryonic lethality, we found that almost 50% of drp‐1 eggs and over 10% of eat‐3 and fzo‐1 eggs fail to hatch indicating an increased rate of embryonic lethality (Figure 3A).…”

Section: Resultsmentioning

confidence: 47%

“…In order to explore the mechanism underlying the increased resistance to stress in the mitochondrial fission and fusion mutants, we hypothesized that the disruption of mitochondrial function triggered an upregulation of stress response pathways as we have observed in long‐lived mitochondrial mutants 20,21,34 . To examine the activation of stress response pathways, we crossed drp‐1, eat‐3, and fzo‐1 to fluorescent reporter strains.…”

Section: Resultsmentioning

confidence: 99%

“…All RNAi clones in these experiments were sequence verified. We have previously shown that the atfs‐1 RNAi clone knocks down the expression of atfs‐1 and its target gene hsp‐6 21 . We have also shown that the daf‐16 RNAi clone phenocopies a daf‐16 mutation 22 .…”

Section: Methodsmentioning

confidence: 92%

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Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

et al. 2020

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Mitochondria are dynamic organelles that can change shape and size depending on the needs of the cell through the processes of mitochondrial fission and fusion. In this work, we investigated the role of mitochondrial dynamics in organismal stress response. By using C. elegans as a genetic model, we could visualize mitochondrial morphology in a live organism with well‐established stress assays and well‐characterized stress response pathways. We found that disrupting mitochondrial fission (DRP1/drp‐1) or fusion (OPA1/eat‐3, MFN/fzo‐1) genes caused alterations in mitochondrial morphology that impacted both mitochondrial function and physiologic rates. While both mitochondrial fission and mitochondrial fusion mutants showed increased sensitivity to osmotic stress and anoxia, surprisingly we found that the mitochondrial fusion mutants eat‐3 and fzo‐1 are more resistant to both heat stress and oxidative stress. In exploring the mechanism of increased stress resistance, we found that disruption of mitochondrial fusion genes resulted in the upregulation of multiple stress response pathways. Overall, this work demonstrates that disrupting mitochondrial dynamics can have opposite effects on resistance to different types of stress. Our results suggest that disruption of mitochondrial fusion activates multiple stress response pathways that enhance resistance to specific stresses.

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Section: Resultsmentioning

confidence: 47%

Section: Resultsmentioning

confidence: 99%

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Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

et al. 2020

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“…We reasoned that transcription factors whose depletion reduce the induction of the UPR mt in sgk-1 mutants might be implicated in the activation of different pro-survival pathways responsible for the long lifespan conferred by PHB depletion to TORC2 mutants [14]. Several transcription factors have been involved in the maintenance of mitochondrial homeostasis and lifespan, including DAF-16, SKN-1, HIF-1 and HSF-1 [34, 40, 51–58]. Moreover, the UPR mt promotes longevity by activating HIF-1, DAF-16 and SKN-1 [58].…”

Section: Resultsmentioning

confidence: 99%

“…Several transcription factors have been involved in the maintenance of mitochondrial homeostasis and lifespan, including DAF-16, SKN-1, HIF-1 and HSF-1 [34, 40, 51–58]. Moreover, the UPR mt promotes longevity by activating HIF-1, DAF-16 and SKN-1 [58]. We checked the involvement of these transcription factors in the activation of the UPR mt in sgk-1 mutants and the essential TORC2 component rict-1.…”

Section: Resultsmentioning

confidence: 99%

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

Hernando‐Rodríguez

Pérez-Jiménez

Rodríguez-Palero

et al. 2019

Preprint

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13 14 -2 -Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar 15 effect on lifespan. While PHB depletion shortens lifespan of wild type animals, it 16 enhances longevity of a plethora of metabolically compromised mutants, 17 including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, 18 we show that sgk-1 mutants have impaired mitochondrial homeostasis, 19 lipogenesis, yolk formation and autophagy flux due to alterations in membrane 20 lipid and sterol homeostasis. Remarkably, all these features are suppressed by 21 PHB depletion. Lifespan analysis shows that autophagy and the mitochondrial 22 unfolded protein response (UPR mt ), but not mitophagy, are required for the 23 enhanced longevity caused by PHB depletion in sgk-1 mutants. We hypothesize 24 that UPR mt induction upon PHB depletion extends lifespan of sgk-1 mutants 25 through autophagy. Our results strongly suggest that PHB depletion suppresses 26 the autophagy defects of sgk-1 mutants by altering membrane lipid composition 27 at ER-mitochondria contact sites, where TORC2 localizes. 28 29 93 mitochondria-associated endoplasmic reticulum (ER) membranes (MAM).94 95 -6 - Results 96Prohibitin depletion suppresses the altered mitochondrial structure and 97 function of sgk-1 mutants 98In C. elegans, loss of function of SGK-1 causes a delay in development (Jones et al., 992009) as well as reduced brood and body size (Soukas et al., 2009). These phenotypes 100 are consistent with phenotypes observed in mitochondrial mutants (Dillin et al., 2002). In 101 addition, worms lacking the TORC2 component RICT-1 or the downstream kinase SGK-102 1, have an induced mitochondrial unfolded protein response (UPR mt ) (Gatsi et al., 2014). 103We analyzed whether mitophagy, another mitochondrial quality control mechanism, 104 might be activated in sgk-1 deletion mutants using a mitophagy reporter based on PINK-105 1 protein (Kirienko et al., 2015). PINK-1 is a serine threonine protein kinase that, when 106 mitochondria are depolarized, accumulates in the outer mitochondrial membrane and 107 targets mitochondria for selective autophagy (Narendra and Youle, 2011; Palikaras et 108 al., 2015). We observed that depletion of sgk-1 increased PINK-1 protein levels ( Figure 109 1A). Similarly, PINK-1 protein levels increased upon depletion of phb-1 or atfs-1, the key 110 UPR mt regulator ( Figure 1A), confirming that sgk-1 mutants suffer from mitochondrial 111 stress. 112To better define the mitochondrial defect of sgk-1 deletion mutants we performed 113 transmission electron microscopy (TEM) analysis. Mitochondria in sgk-1 mutants were 114 swollen, and bigger compared to wild type worms in all tissues analyzed (hypodermis, 115 muscle and intestine) at both, day one and day five of adulthood ( Figure 1B and Figure 116 S1A, respectively). In contrast to previous observations (Zhou et al., 2019), no obvious 117 mitochondrial fragmentation or severe cristae defects in the intestine were observed in 118 the TEM sections analyzed. 119-7 -To ...

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Mitophagy in aging and longevity

Guo

Chiang

2021

IUBMB Life

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The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.

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Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways

Cited by 87 publications

References 55 publications

Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

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

Mitophagy in aging and longevity

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