A mechanistic review of Parkin activation

Gundogdu, Mehmet; Tadayon, Roya; Salzano, Giulia; Shaw, Gary S.; Walden, Helen

doi:10.1016/j.bbagen.2021.129894

Cited by 21 publications

(17 citation statements)

References 82 publications

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“…Our previous report indicated that substrates of parkin are involved in many important cellular physiologic processes, including apoptosis, mitochondrial metabolism, and protein clearance [66]. In this study, we found that the protein expression of ARTS, one of the substrates of parkin, is down-regulated by PMN.…”

Section: Discussionsupporting

confidence: 49%

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Hsu

Hung

Tsai

et al. 2021

IJMS

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Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

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Section: Discussionsupporting

confidence: 49%

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Hsu

Hung

Tsai

et al. 2021

IJMS

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“…A recurring model of parkin activity has posited that parkin forms dimers or oligomers to allow the catalytic RING2 domain of one molecule to contact the E2~Ub bound to another molecule (Gundogdu et al , 2021 ). We previously showed an absence of complementation in autoubiquitination assays (Sauve et al , 2018 ), but this left open the possibility of trans ‐active parkin dimers on the surface of mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for feedforward control in the PINK1/Parkin pathway

et al. 2022

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PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson's disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin-like (Ubl) domain of parkin. Here, we observed that phospho-ubiquitin can bind to two distinct sites on parkin, a high-affinity site on RING1 that controls parkin localization and a low-affinity site on RING0 that releases parkin autoinhibition. Surprisingly, ubiquitin vinyl sulfone assays, ITC, and NMR titrations showed that the RING0 site has higher affinity for phospho-ubiquitin than phosphorylated Ubl in trans. We observed parkin activation by micromolar concentrations of tetra-phospho-ubiquitin chains that mimic mitochondria bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1-parkin pathway and likely represents an intermediate step in its evolutionary development.

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“…Therefore, PINK1 plays a role as ubiquitin kinase. A recent review goes into depth on the structural findings regulating Parkin activity [ 81 ]. PINK1 acts as a mitochondrial damage sensor, and when its import is arrested (under bioenergetics stress, loss in ∆Ψ m ), it accumulates on the OMM of dysfunctional mitochondria and phosphorylates Ub molecules (pUb).…”

Section: Regulation Of Mitophagymentioning

confidence: 99%

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

Iorio

Celenza

Petricca

2021

Cells

107

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Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5′-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1–Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.

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A mechanistic review of Parkin activation

Cited by 21 publications

References 82 publications

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Structural basis for feedforward control in the PINK1/Parkin pathway

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

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