Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response

Berry, Brandon J.; Nieves, Tyrone; Wojtovich, Andrew P.

doi:10.17912/micropub.biology.000445

Cited by 4 publications

(6 citation statements)

References 13 publications

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“…Since paraquat induces the mitochondrial unfolded protein response, UPRmt, in C. elegans [24,78], the results of Dilberger et al [69] suggest that the activation of mPTP is sufficient to activate UPRmt. Berry et al [24] also showed that reduction in ∆Ψm by the uncoupler FCCP was sufficient to activate UPRmt in C. elegans. However, FCCP is known to activate mPTP [75], and Angeli et al [79] showed that genetic or pharmacological inhibition of mPTP inhibited UPRmt.…”

Section: Mitochondrial Membrane Potential and Aging In C Elegansmentioning

confidence: 99%

“…Interestingly, in their study, Berry et al [24] measured ∆Ψm from TMRE fluorescence from the whole body of the worms after incubating the worms for 24 h with 100 nM TMRE. It appears, however, that at this high TMRE concentration, the dye in the mitochondrial matrix was largely aggregated and largely quenched.…”

Section: Mitochondrial Membrane Potential and Aging In C Elegansmentioning

confidence: 99%

“…Another often reported mitochondrial dysfunction in aging is reduction in the magnitude of ∆Ψm (reviewed in [21][22][23]. It was recently suggested that the reduction in ∆Ψm in aged animals is a major cause of aging [23][24][25][26][27]-this claim was supported by the demonstration that the optogenetic-induced increase of ∆Ψm increased C. elegans lifespan [25]-and that calorie restriction that increases C. elegans lifespan restores ∆Ψm in aged animals [26]. In animal cells ∆Ψm varies within a narrow range (−130 to −180 mV); many metabolic functions affect the magnitude of ∆Ψm.…”

Section: Introductionmentioning

confidence: 99%

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The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

Rottenberg

2023

IJMS

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It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP. Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and mROS, and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively.

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Section: Mitochondrial Membrane Potential and Aging In C Elegansmentioning

confidence: 99%

Section: Mitochondrial Membrane Potential and Aging In C Elegansmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

Rottenberg

2023

IJMS

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“…It has been previously described that reduction in MMP can alter the import properties of proteins and thereby trigger cellular signaling events related to mitophagy, transcriptional responses, and others ( Becker et al, 2012 . ; Berry et al, 2021 . ; Jin et al, 2010 ; Miceli et al, 2011 ; Rolland et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms

Ouyang,

Jeong,

Cunningham

et al. 2024

eLife

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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 mitochondrial membrane potential is 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 function even in defective mitochondria.

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“…Conversely, recent studies have examined specific stressors that stimulate the UPRmt and mitophagy simultaneously, such as muscle denervation, which induces the UPRmt and mitophagy-related protein activity [37], and high-fat diet-induced acute insulin resistance, which synchronously increases the UPRmt and mitophagy-related protein expression in mouse skeletal muscle [38]. The overexpression of mutant ornithine transcarbamylase in HeLa cells activates the UPRmt and mitophagy without affecting the membrane potential [39] and disrupted mitochondrial protein import and membrane depolarization also trigger both the UPRmt and mitophagy pathways [40,41].…”

Section: Relationship Between the Uprmt And Mitophagymentioning

confidence: 99%

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Wang

Zhang

et al. 2023

Life

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The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.

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Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response

Cited by 4 publications

References 13 publications

The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

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