Optogenetic rejuvenation of mitochondrial membrane potential extends<i>C. elegans</i>lifespan

Berry, Brandon J.; Vodičková, Anežka; Müller-Eigner, Annika; Meng, Chen; Ludwig, Christina; Kaeberlein, Matt; Peleg, Shahaf; Wojtovich, Andrew P.

doi:10.1101/2022.05.11.491574

Cited by 5 publications

(3 citation statements)

References 28 publications

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“…From the evidence presented herein, as well as the previous study showing that PFA treatment extends lifespan in flies (Bergwitz et al, 2013), we hypothesize that phosphate deprivation increased MMP and overall mitochondrial health, and thereby enabled lifespan extension. This connection is supported by a recent study that demonstrated that boosting MMP by photo-activation of an ectopically expressed proton pump is sufficient to prolong lifespan in C. elegans (Berry et al, 2022).…”

Section: Discussionmentioning

confidence: 68%

“…While it is likely that MMP reduction plays a causal role in the pathogenesis of these diseases, the tools to formally test its impact on each disease are limited. In the context of aging, activating an artificial proton pump in C. elegans restores the loss of MMP typical of aging and is sufficient to extend lifespan (Berry et al, 2022), which suggests causality in this case. In addition, using the same manipulation to ectopically increase MMP improves the survival of C. elegans treated with electron transport chain inhibitors (Berry et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

Ouyang

Cunningham

Berg

et al. 2022

Preprint

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Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of the mitochondrial membrane potential is also observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial functions even with defective mitochondria.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

Ouyang

Cunningham

Berg

et al. 2022

Preprint

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“…daf-2 mutants and several other long-lived mutants were shown to have lower mitochondrial membrane potential than wild-type worms, though others have reported the opposite [60,61,90]. Mitochondrial membrane potential decreases with age [91] and preventing this decline is sufficient to increase lifespan [92]. Moreover, dietary restriction appears to increase lifespan at least partially through the preservation of the mitochondrial membrane potential [93].…”

Section: Disruption Of Drp-1 Does Not Affect Mitochondrial Membrane P...mentioning

confidence: 99%

Developmental disruption of the mitochondrial fission genedrp-1extends the longevity ofdaf-2insulin/IGF-1 receptor mutant

Traa,

Van Raamsdonk

2024

Preprint

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The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell's ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. While disruption of the mitochondrial fission gene drp-1 only mildly increases wild-type lifespan, it drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with a number of different RNAi clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses and slows physiologic rates in daf-2 worms. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels or mitochondrial membrane potential. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

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Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction

et al. 2023

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Optogenetic rejuvenation of mitochondrial membrane potential extendsC. eleganslifespan

Cited by 5 publications

References 28 publications

Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

Developmental disruption of the mitochondrial fission genedrp-1extends the longevity ofdaf-2insulin/IGF-1 receptor mutant

Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction

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