Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination

Ham, Su Jin; Lee, Daewon; Yoo, Heesuk; Jun, Kyoungho; Shin, Hyeonjoon; Chung, Jongkyeong

doi:10.1073/pnas.1909814117

Cited by 138 publications

(104 citation statements)

References 63 publications

(62 reference statements)

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“…Alterations in mitochondrial calcium uptake can lead to oxidative stress or calcium overload triggering cell death (72)(73)(74). Interestingly, several recent studies have revealed a role of increased mitochondrial calcium levels in promoting neurodegenerative phenotypes (75)(76)(77)(78)(79). For example, in Drosophila and zebra sh, it was found that mutations in the genes encoding the PINK1 ortholog results in elevated mitochondrial calcium, and when mitochondrial calcium was reduced in these mutants neurodegeneration was prevented (80,81).…”

Section: Discussionmentioning

confidence: 99%

Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

Ryan

Ashkavand

Sarasija

et al. 2020

Preprint

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BackgroundMetabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease, such as Alzheimer’s disease (AD). However, the mechanisms underlying these abnormalities remain poorly understood. Mutations in the presenilin genes are the primary cause of early onset familial AD, but despite their identification over 20 years ago, their role in the disease remains unclear. MethodsThe model system Caenorhabditis elegans was utilized to study the in vivo function of the highly conserved presenilin ortholog SEL-12 in the nervous system. Cell biological and biochemical assays were employed to monitor changes to proteostasis and autophagic flux in sel-12 mutants. Immunoblotting was used to assess alterations to the activity of the mTORC1 pathway, a central inhibitor of autophagy. Genetic and pharmaceutical strategies to reduce mTORC1 activity, and fluorescent reporters and biosensors were expressed in the mechanosensory neurons to measure mTORC1’s influence on proteotoxicity, neuronal health and mitochondrial morphology. Additionally, behavioral response to touch was employed to determine the role mTORC1 activity has in neuronal function in sel-12 mutants. RNA interference by standard feeding methods was used to assess the contribution of autophagy to mTORC1-mediated sel-12 defects. ResultsLoss of SEL-12 results in the hyperactivation of the mTORC1 pathway and mTORC1-dependent reduction in autophagy. This hyperactivation is caused by elevated mitochondrial calcium signaling and concomitant mitochondrial hyperactivity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagy, and this reduction is prevented by limiting mitochondrial calcium uptake or mitochondrial respiration. Moreover, the improvements in proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy.ConclusionSEL-12 has a critical role in mediating mitochondrial calcium homeostasis and activity. In the absence of presenilin function mitochondrial calcium uptake and mitochondrial activity is increased. This mitochondrial hyperactivity stimulates mTORC1 signaling, which inhibits autophagy and promotes proteostasis decline and neuronal dysfunction in sel-12 mutants. These data suggest that the mTORC1 pathway is a potential therapeutic target for treating AD.

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Section: Discussionmentioning

confidence: 99%

Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

Ryan

Ashkavand

Sarasija

et al. 2020

Preprint

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“…Interestingly, beyond compensatory or synergistic effects, the ubiquitylation state of VDAC was shown to differentially affect either mitophagy or apoptosis. While polyubiquitylated VDAC1 is able to induce mitophagy, monoubiquitylated VDAC1 seems to exert a protective effect over apoptosis (Ham et al, 2020). However, the conditions by which VDAC gets mono or polyubiquitylated and the respective E3 ligases involved are still to be identified.…”

Section: Pro-apoptotic Effects Of Mitophagymentioning

confidence: 99%

Role of Mitofusins and Mitophagy in Life or Death Decisions

Joaquim

Escobar-Henriques

2020

Front. Cell Dev. Biol.

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Mitochondria entail an incredible dynamism in their morphology, impacting death signaling and selective elimination of the damaged organelles. In turn, by recycling the superfluous or malfunctioning mitochondria, mostly prevalent during aging, mitophagy contributes to maintain a healthy mitochondrial network. Mitofusins locate at the outer mitochondrial membrane and control the plastic behavior of mitochondria, by mediating fusion events. Besides deciding on mitochondrial interconnectivity, mitofusin 2 regulates physical contacts between mitochondria and the endoplasmic reticulum, but also serves as a decisive docking platform for mitophagy and apoptosis effectors. Thus, mitofusins integrate multiple bidirectional inputs from and into mitochondria and ensure proper energetic and metabolic cellular performance. Here, we review the role of mitofusins and mitophagy at the crossroad between life and apoptotic death decisions. Furthermore, we highlight the impact of this interplay on disease, focusing on how mitofusin 2 and mitophagy affect non-alcoholic fatty liver disease.

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“…Parkin has been reported to specifically target the pro-survival BCL-2 protein MCL-1 for proteosomal degradation (Figure 4; Carroll et al 2014;Zhang et al 2014). In a recent study, Ham et al (2020) propose that the decision between mitophagy or apoptosis induction by Parkin depends on the ubiquitination of VDAC (Figure 4; Ham et al 2020). It has been proposed that Parkin either mono-or polyubiquitinates VDAC1.…”

Section: Parkin Activation Can Both Prevent and Promote Cell Deathmentioning

confidence: 99%

Kill one or kill the many: interplay between mitophagy and apoptosis

Wanderoy

Hees

Klesse

et al. 2020

Biological Chemistry

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Mitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson’s disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of pro-apoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system.

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Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination

Cited by 138 publications

References 63 publications

Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

Role of Mitofusins and Mitophagy in Life or Death Decisions

Kill one or kill the many: interplay between mitophagy and apoptosis

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