Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson’s Disease

Abstract

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Major contributors to the sporadic form of the disease, in addition to aging, are exposure to pesticides and other toxins such as rotenone, paraquat and MPP+ that increase ROS production and activate mPTP [ 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 ]. The familial forms of Parkinson’s disease result from mutations in a number of proteins: mitochondrial proteins that participate in mitophagy, PINK1 and Parkin [ 186 , 227 ], LRRK2, a protein that participates in fission [ 228 , 229 , 230 , 231 ], several ATG proteins that participate in autophagy [ 212 ] and α-synuclein [ 231 ]. Thus, the majority of the familial forms of the disease result from mutations in proteins that participate in different stages of mitophagy/autophagy, indicating that the disruption of mitophagy is a major cause of the familial form of the disease [ 212 ].…”

“…The ROS-induced activation of mPTP in the electron transport inhibitor model (MPTP + ) of Parkinson’s disease leads to activation of the NLRP3 inflammasome, resulting in the loss of dopaminergic neurons [ 164 , 205 ]. It is therefore increasingly evident that Parkinson’s disease, in all of its manifestations, is caused either by the inhibition of mitophagy (which fails to remove activated mPTP) [ 169 , 170 , 186 , 192 , 215 , 227 , 236 ] or by the excessive activation of mPTP [ 164 , 235 ], as summarized in Figure 3 . Aging enhances the production of mROS and this can increase mPTP activation directly or through oxidative damage to α-synuclein.…”

The Role of Glial Mitochondria in α-Synuclein Toxicity

“…Moreover, mutations in α-syn (duplications, triplications, or point mutations) facilitate aggregate formation in neurons and affect the exacerbation and progression of PD. Many pathological features of PD, such as mitochondrial dysfunction ( Park et al, 2018 ; Wang X.L. et al, 2020 ), neuroinflammation ( Wang et al, 2015 ; Pajares et al, 2020 ), ER stress ( Colla, 2019 ), and impaired protein quality control ( Cook and Petrucelli, 2009 ; Sala et al, 2016 ), can lead to neuronal toxicity.…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Major contributors to the sporadic form of the disease, in addition to aging, are exposure to pesticides and other toxins such as rotenone, Paraquat and MPP+ that increase ROS production and activate mPTP (218 -225). The familial forms of Parkinson's disease result from mutations in a number of proteins: mitochondrial proteins that participate in mitophagy, PINK1 and Parkin (185,226), LRKK2, a protein that participates in fission (227 -230), several ATG proteins that participate in autophagy (211), and α-synuclein (230). Thus, the majority of the familial forms of the disease results from mutations in proteins that participate in different stages of mitophagy/autophagy, indicating that disruption of mitophagy is a major cause of the familial form of the disease (211).…”

“…The ROS-induced activation of mPTP in the electron transport inhibitor model (MPTP + ) of Parkinson's Disease leads to activation of the NLRP3 inflammasome resulting in the loss of dopaminergic neurons (163,204). It is therefore increasingly evident that Parkinson's Disease, in all of its manifestation, is caused either by inhibition of mitophagy (which fails to remove activated mPTP) ( 168,169,185,191,214,226,235) or by excessive clearence of mitochondria by excess activation of mPTP (163,234). Aging enhances the production of mROS and this can increase mPTP activation directly or through oxidative damage to α-synuclein.…”