Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

Labbadia, Johnathan; Brielmann, Renée M.; Neto, Mário F.; Lin, Yi; Haynes, Cole M.; Morimoto, Richard I.

doi:10.1016/j.celrep.2017.10.038

Cited by 143 publications

(134 citation statements)

References 60 publications

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“…Our work and others have shown that mutations leading to mild impairment of mitochondrial function can result in increased lifespan 35,62‐64 and increased resistance to stress 20,21,34,65 . At least in some of these mutants, our results indicated that the activation of stress response pathways, namely, the mitoUPR, is required for both the increase in lifespan and resistance to stress 21 …”

Section: Discussionsupporting

confidence: 58%

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: Discussionsupporting

confidence: 58%

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

et al. 2020

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“…The mitochondrial ET-pathway has been recently identified as a central regulator of the age-related decline of heat shock response and cytosolic proteostasis. A mild down-regulation of complex IV activity at an early age in the nematodes Caenorhabditis elegans results in an increased vitality later in life due to an increase in the sensitivity to protein misfolding through regulation of HSF-1 [87]. The pattern of complex IV activation in the NRs might be indicative of change in the cardiac aging process associated with the diet.…”

Section: Discussionmentioning

confidence: 99%

Age and sex as confounding factors in the relationship between cardiac mitochondrial function and type 2 diabetes in the Nile Grass rat

et al. 2020

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Our study revisits the role of cardiac mitochondrial adjustments during the progression of type 2 diabetes mellitus (T2DM), while considering age and sex as potential confounding factors. We used the Nile Grass rats (NRs) as the animal model. After weaning, animals were fed either a Standard Rodent Chow Diet (SRCD group) or a Mazuri Chinchilla Diet (MCD group) consisting of high-fiber and low-fat content. Both males and females in the SRCD group, exhibited increased body mass, body mass index, and plasma insulin compared to the MCD group animals. However, the females were able to preserve their fasting blood glucose throughout the age range on both diets, while the males showed significant hyperglycemia starting at 6 months in the SRCD group. In the males, a higher citrate synthase activity-a marker of mitochondrial content-was measured at 2 months in the SRCD compared to the MCD group, and this was followed by a decline with age in the SRCD group only. In contrast, females preserved their mitochondrial content throughout the age range. In the males exclusively, the complex IV capacity expressed independently of mitochondrial content varied with age in a diet-specific pattern; the capacity was elevated at 2 months in the SRCD group, and at 6 months in the MCD group. In addition, females, but not males, were able to adjust their capacity to oxidize long-chain fatty acid in accordance with the fat content of the diet. Our results show clear sexual dimorphism in the variation of mitochondrial content and oxidative phosphorylation capacity with diet and age. The SRCD not only leads to T2DM but also exacerbates age-related cardiac mitochondrial defects. These observations, specific to male NRs, might reflect deleterious dietary-induced changes on their metabolism making them more prone to the cardiovascular consequences of aging and T2DM.

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“…5g-i). All promote the expression of various chaperones 45 or unfolded protein response (UPR) activation to promote stress resistance 46,47 . ire-1 expression was also enriched in our transcriptomic analysis in SH-SY5Y cells, and it has been shown that NRF2 can promote its activation upon oxidative stress 41,48 .…”

Section: Elegansmentioning

confidence: 99%

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling

Tauffenberger

Fiumelli

Almustafa

et al. 2019

Preprint

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Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

Cited by 143 publications

References 60 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

Age and sex as confounding factors in the relationship between cardiac mitochondrial function and type 2 diabetes in the Nile Grass rat

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling

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