PINK1 Content in Mitochondria is Regulated by ER-Associated Degradation

Guardia‐Laguarta, Cristina; Liu, Yuhui; Lauritzen, Knut H.; Erdjument‐Bromage, Hediye; Martin, Brittany M. St.; Swayne, Theresa C.; Jiang, Xuejun; Przedborski, Serge

doi:10.1523/jneurosci.1691-18.2019

Cited by 48 publications

(36 citation statements)

References 75 publications

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“…2 c). These facilitate PINK1’s ubiquitination allowing valosin containing proteins, UFD1 and UFD2A, to target PINK1 for proteasomal degradation [ 77 ]. Other proteases such as matrix-AAA and caseinolytic mitochondrial matrix peptidase (ClpXP) can cleave PINK1.…”

Section: Main Textmentioning

confidence: 99%

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

261

136

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Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson’s disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer’s diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma.

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Section: Main Textmentioning

confidence: 99%

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

261

136

View full text Add to dashboard Cite

show abstract

“…Moreover, α-synuclein was found in MERCs from mouse and human brain tissue, where it seems to modulate mitochondrial morphology (78). Like α-synuclein, PINK1 was recently found to also localize to MERCs, and its continuous degradation in healthy mitochondria is regulated by the interplay of mitochondria and the ER (79). It is worth noting that the PD-related proteins PINK1, Parkin, LRRK2, and α-synuclein that are involved in MERCs have also been shown to directly or indirectly interact with Miro1 (7,11,12,21).…”

Section: Miro1 As a Regulator Of Mitochondrial-er Contact Sitesmentioning

confidence: 99%

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

et al. 2020

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The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying molecular pathogenesis. Here, first insights provided by genetics over the last two decades, such as dysfunction of molecular and organellar quality control, are described. The mechanisms involved relate to impaired intracellular calcium homeostasis and mitochondrial dynamics, which are tightly linked to the cross talk between the endoplasmic reticulum (ER) and mitochondria. A number of proteins related to monogenic forms of PD have been mapped to these pathways, i.e., PINK1, Parkin, LRRK2, and α-synuclein. Recently, Miro1 was identified as an important player, as several studies linked Miro1 to mitochondrial quality control by PINK1/Parkin-mediated mitophagy and mitochondrial transport. Moreover, Miro1 is an important regulator of mitochondria-ER contact sites (MERCs), where it acts as a sensor for cytosolic calcium levels. The involvement of Miro1 in the pathogenesis of PD was recently confirmed by genetic evidence based on the first PD patients with heterozygous mutations in RHOT1/Miro1. Patient-based cellular models from RHOT1/Miro1 mutation carriers showed impaired calcium homeostasis, structural alterations of MERCs, and increased mitochondrial clearance. To account for the emerging role of Miro1, we present a comprehensive overview focusing on the role of this protein in PD-related neurodegeneration and highlighting new developments in our understanding of Miro1, which provide new avenues for neuroprotective therapies for PD patients.

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“…It can be introduced into the mitochondrial membrane space and degraded by proteases on the inner mitochondrial membrane to maintain the basic level (38). However, when mitochondria are damaged and depolarized, their ability to degrade PINK1 is weakened, and PINK1 can stably exist on the outer mitochondrial membrane (39). Then, it can phosphorylate both ubiquitin and Parkin to recruit Parkin from the cytoplasm to the outer mitochondrial membrane (40).…”

Section: Parkin-dependent Mitophagy Pathwaymentioning

confidence: 99%

The Role of Mitophagy in Ischemic Stroke

et al. 2020

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Mitochondria are important places for eukaryotes to carry out energy metabolism and participate in the processes of cell differentiation, cell information transmission, and cell apoptosis. Autophagy is a programmed intracellular degradation process. Mitophagy, as a selective autophagy, is an evolutionarily conserved cellular process to eliminate dysfunctional or redundant mitochondria, thereby fine-tuning the number of mitochondria and maintaining energy metabolism. Many stimuli could activate mitophagy to regulate related physiological processes, which could ultimately reduce or aggravate the damage caused by stimulation. Stroke is a common disease that seriously affects the health and lives of people around the world, and ischemic stroke, which is caused by cerebral vascular stenosis or obstruction, accounts for the vast majority of stroke. Abnormal mitophagy is closely related to the occurrence, development and pathological mechanism of ischemic stroke. However, the exact mechanism of mitophagy involved in ischemic stroke has not been fully elucidated. In this review, we discuss the process and signal pathways of mitophagy, the potential role of mitophagy in ischemic stroke and the possible signal transduction pathways. It will help deepen the understanding of mitophagy and provide new ideas for the treatment of ischemic stroke.

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PINK1 Content in Mitochondria is Regulated by ER-Associated Degradation

Cited by 48 publications

References 75 publications

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

The Role of Mitophagy in Ischemic Stroke

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