Insights Into Parkin-Mediated Mitophagy in Alzheimer's Disease: A Systematic Review

Goudarzi, Sepideh; Hosseini, Asieh; Abdollahi, Mohammad; Haghi‐Aminjan, Hamed

doi:10.3389/fnagi.2021.674071

Cited by 22 publications

(16 citation statements)

References 32 publications

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“…Taken together, it seems to reveal that under the ApoE4 condition, the proportion of FL-PINK1 is increased and the proportion of cleaved PINK1 is accordingly decreased at the basic of the reductive total amount of PINK1. These observations echo the alterations in AD abovementioned (Mise et al, 2017 ; Ochi et al, 2020 ; Goudarzi et al, 2021 ). Additionally, ApoE4 rather than ApoE3 astrocytes demonstrate lower level of PINK1 upregulation caused by MG-132 (Schmukler et al, 2020 ), similarly indicating an impaired degradation caused by ApoE4.…”

Section: Apoe4 and Mitophagy-specific Processes In Adsupporting

confidence: 85%

“…Both PINK1 and Parkin have been widely investigated not only in PD but also in AD (El Gaamouch et al, 2016 ; Martín-Maestro et al, 2016 ). The levels of PINK1 and Parkin, as well as the related factors, are usually remarkably increased in vivo and in vitro models of AD and patients with AD (Mise et al, 2017 ; Ochi et al, 2020 ; Goudarzi et al, 2021 ), indicating various mitochondrial disturbances or dysfunctional mitophagy. However, the additional finding indicates upregulation of PINK1-Parkin-mediated mitophagy signaling improves cognitive behavior and memory in rats injected with Aβ 1−42 (Han et al, 2020 ).…”

Section: Apoe4 and Mitophagy-specific Processes In Admentioning

confidence: 99%

“…Aβ aggregation causes reductive cytosolic Parkin and PINK1 levels in the cytoplasm (Kerr et al, 2017 ); Aβ also binding to Parkin and autophagic vacuoles in the distal axons of APP-mutant mouse cells (Cai and Tammineni, 2016 ; Reddy and Oliver, 2019 ). Presenilins mutations interrupt PINK1 elevation and PINK/Parkin-dependent mitophagic cycle (Goudarzi et al, 2021 ). More Parkin recruitment of cytosolic to depolarized mitochondria is shown in human APP-transgenic neurons (Cai and Tammineni, 2016 ).…”

Section: Apoe4 and Mitophagy-specific Processes In Admentioning

confidence: 99%

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A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

Chen

Jiang

et al. 2022

Front. Aging Neurosci.

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Alzheimer's disease (AD) is one of the major worldwide causes of dementia that is characterized by irreversible decline in learning, memory loss, and behavioral impairments. Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years. APOE ε4 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic (DRP1, MFN-1), mitophagic induction (PINK1, Parkin). These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.

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Section: Apoe4 and Mitophagy-specific Processes In Adsupporting

confidence: 85%

Section: Apoe4 and Mitophagy-specific Processes In Admentioning

confidence: 99%

Section: Apoe4 and Mitophagy-specific Processes In Admentioning

confidence: 99%

See 1 more Smart Citation

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

Chen

Jiang

et al. 2022

Front. Aging Neurosci.

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“…Pink1 (PTEN-induced kinase 1) is a mitochondrial inner membrane kinase, which is degraded under the functioning mitochondria [ 25 ]. However, upon mitochondrial membrane damage/depolarization, Pink1 is retained in the outer mitochondrial membrane and phosphorylates outer membrane proteins, such as VDAC1 (voltage-dependent anion-selective channel 1) and Mfn2 (mitofusin 2), which are recognized by Parkin, an E3 ubiquitin ligase, for ubiquitination [ 16 , 26 , 27 ]. Then, mitophagy adaptors optineurin/p62-sequestosome1 and LC3B-II (microtubule-associated proteins 1A/1B light chain 3B) in double membrane autophagophore form the mitophagosome, inside of which damaged mitochondria are enclosed [ 20 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy

Singh

Devi

2021

Diseases

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Chronic hyperglycemia-induced thioredoxin-interacting protein (TXNIP) expression, associated oxidative/nitrosative stress (ROS/RNS), and mitochondrial dysfunction play critical roles in the etiology of diabetic retinopathy (DR). However, there is no effective drug treatment to prevent or slow down the progression of DR. The purpose of this study is to examine if a combination drug treatment targeting TXNIP and the mitochondria-lysosome pathway prevents high glucose-induced mitochondrial stress and mitophagic flux in retinal Müller glial cells in culture, relevant to DR. We show that diabetes induces TXNIP expression, redox stress, and Müller glia activation (gliosis) in rat retinas when compared to non-diabetic rat retinas. Furthermore, high glucose (HG, 25 mM versus low glucose, LG 5.5 mM) also induces TXNIP expression and mitochondrial stress in a rat retinal Müller cell line, rMC1, in in vitro cultures. Additionally, we develop a mitochondria-targeted mCherry and EGFP probe tagged with two tandem COX8a mitochondrial target sequences (adenovirus-CMV-2×mt8a-CG) to examine mitophagic flux in rMC1. A triple drug combination treatment was applied using TXNIP-IN1 (which inhibits TXNIP interaction with thioredoxin), Mito-Tempo (mitochondrial anti-oxidant), and ML-SA1 (lysosome targeted activator of transient calcium channel MCOLN1/TRPML1 and of transcription factor TFEB) to study the mitochondrial–lysosomal axis dysregulation. We found that HG induces TXNIP expression, redox stress, and mitophagic flux in rMC1 versus LG. Treatment with the triple drug combination prevents mitophagic flux and restores transcription factor TFEB and PGC1α nuclear localization under HG, which is critical for lysosome biosynthesis and mitogenesis, respectively. Our results demonstrate that 2×mt8a-CG is a suitable probe for monitoring mitophagic flux, both in live and fixed cells in in vitro experiments, which may also be applicable to in vivo animal studies, and that the triple drug combination treatment has the potential for preventing retinal injury and disease progression in diabetes.

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“…Deletion of mitochondrial ubiquitin ligase, which is involved in mitochondrial dynamics and functions and is dysregulated in AD, initiates mitochondrial impairments and worsens cognitive decline in a mouse model with AD-related Aβ pathology [ 48 ]. Other studies have examined the triggering of apoptotic cascades and organelle swelling following exposure of mitochondria to Aβ [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

Section: Mitochondrial Impairment In Admentioning

confidence: 99%

Disentangling Mitochondria in Alzheimer’s Disease

Johri

2021

IJMS

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Alzheimer’s disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments are available. AD has a complex etiology, although mitochondrial dysfunction, oxidative stress, inflammation, and metabolic abnormalities have been widely and deeply investigated as plausible mechanisms for its neuropathology. Aβ plaques and hyperphosphorylated tau aggregates, along with cognitive deficits and behavioral problems, are the hallmarks of the disease. Restoration of mitochondrial bioenergetics, prevention of oxidative stress, and diet and exercise seem to be effective in reducing Aβ and in ameliorating learning and memory problems. Many mitochondria-targeted antioxidants have been tested in AD and are currently in development. However, larger streamlined clinical studies are needed to provide hard evidence of benefits in AD. This review discusses the causative factors, as well as potential therapeutics employed in the treatment of AD.

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Insights Into Parkin-Mediated Mitophagy in Alzheimer's Disease: A Systematic Review

Abstract: Graphical AbstractInteractions of PINK1/Parkin pathway with AD-related proteins.

Cited by 22 publications

References 32 publications

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy

Disentangling Mitochondria in Alzheimer’s Disease

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