Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling

Norris, Kristi L.; Hao, Rui; Chen, Liangfu; Lai, Chun-Hsiang; Kapur, Meghan; Shaughnessy, Peter J.; Chou, Dennis; Jin, Yan; Taylor, J. Paul; Engelender, Simone; West, Anna E.; Lim, Kah‐Leong; Yao, Tso‐Pang

doi:10.1074/jbc.m114.634063

Cited by 79 publications

(75 citation statements)

References 46 publications

(43 reference statements)

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“…Some recent studies have indicated that PINK1 accumulation, along with Parkin recruitment on damaged mitochondria, depends on the bioenergetic state of the cell, and ATP may have a key involvement in this process 132,133. Furthermore, other studies have indicated complex interactions of Parkin, PINK1 and α-synuclein in regulating mitochondrial dynamics and mitophagy 134,135. Overall, it appears that altered mitophagy and mitochondrial dynamics play a key role in PD pathogenesis, with the involvement of Parkin, PINK1 and α-synuclein, but the molecular scenario is far from clear as of now.…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Ganguly¹,

Chakrabarti²,

Chatterjee³

et al. 2017

DDDT

248

185

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Alzheimer’s disease and Parkinson’s disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson’s disease are primarily motor deficits, while the patients of Alzheimer’s disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer’s disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson’s disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins – as oligomers or in aggregated forms – cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.

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Section: Parkinson’s Diseasementioning

confidence: 99%

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Ganguly¹,

Chakrabarti²,

Chatterjee³

et al. 2017

DDDT

248

185

View full text Add to dashboard Cite

show abstract

“…Under moderate stress conditions PINK1 and Parkin reportedly regulate generation of mitochondria-derived vesicles to degrade oxidized mitochondrial components [20]. Similarly, low dose treatment with the mitochondrial uncoupler CCCP results in Parkin-mediated fusion, which limits mitochondrial damage and thus mitophagy in neurons [21] (see next paragraph). Higher doses of CCCP reportedly promote Parkin recruitment and mitophagy, which is antagonized by Parkin interaction with antiapoptotic Bcl-2 proteins (Bcl-xL, Mcl-1, Bcl-w) [22**].…”

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

Regulators of mitochondrial dynamics in cancer

Senft

Ronai

2016

Current Opinion in Cell Biology

222

230

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Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in physiological conditions and are often deregulated in cancer. Mitochondrial protein homeostasis, transcriptional regulation, and post-translational modification are among processes that govern the control of mitochondrial dynamics. Cancer cells alter mitochondrial dynamics to resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiating and transformation properties including proliferation, migration, and therapeutic resistance. This review focuses on key regulators of mitochondrial dynamics and their role in cancer.

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“…PARK2 controls the cell cycle by acting as a master regulator of multiple G1/S cyclins. Using systems mainly geared towards examining neural biology, several studies have shown that PARK2 plays a role in mitochondrial maintenance and turnover [12], [13], [14]. However, the full extent of PARK2’s functions and how inactivation of PARK2 promotes tumor growth is unknown.…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis

Gong

Schumacher

et al. 2017

Neoplasia

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Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.

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Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling

Cited by 79 publications

References 46 publications

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Regulators of mitochondrial dynamics in cancer

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis

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Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling

Cited by 79 publications

References 46 publications

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer&#39;s disease and Parkinson&#39;s disease

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer&#39;s disease and Parkinson&#39;s disease

Regulators of mitochondrial dynamics in cancer

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis

Contact Info

Product

Resources

About

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease