Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cai, Qian; Jeong, Yu Young

doi:10.3390/cells9010150

Cited by 182 publications

(116 citation statements)

References 260 publications

(338 reference statements)

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“…Next, we examined whether Rheb‐associated mitophagy requires Nix, an outer mitochondrial membrane protein (Youle & Narendra, ; Cai & Jeong, ). Utilizing Nix shRNA that was previously described (Fei et al , ; Melser et al , ), we found that Nix RNAi results in markedly reduced localization of Rheb to axonal mitochondria upon Δψ m dissipation (Scrambled shRNA: 38.83% ± 1.34%; Nix shRNA: 23.31% ± 1.26%; P < 0.001; Fig EV1G and H).…”

Section: Resultsmentioning

confidence: 99%

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

et al. 2020

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Synaptic mitochondria are particularly vulnerable to physiological insults, and defects in synaptic mitochondria are linked to early pathophysiology of Alzheimer's disease (AD). Mitophagy, a cargo‐specific autophagy for elimination of dysfunctional mitochondria, constitutes a key quality control mechanism. However, how mitophagy ensures synaptic mitochondrial integrity remains largely unknown. Here, we reveal Rheb and Snapin as key players regulating mitochondrial homeostasis at synapses. Rheb initiates mitophagy to target damaged mitochondria for autophagy, whereas dynein–Snapin‐mediated retrograde transport promotes clearance of mitophagosomes from synaptic terminals. We demonstrate that synaptic accumulation of mitophagosomes is a feature in AD‐related mutant hAPP mouse brains, which is attributed to increased mitophagy initiation coupled with impaired removal of mitophagosomes from AD synapses due to defective retrograde transport. Furthermore, while deficiency in dynein–Snapin‐mediated retrograde transport recapitulates synaptic mitophagy stress and induces synaptic degeneration, elevated Snapin expression attenuates mitochondrial defects and ameliorates synapse loss in AD mouse brains. Taken together, our study provides new insights into mitophagy regulation of synaptic mitochondrial integrity, establishing a foundation for mitigating AD‐associated mitochondria deficits and synaptic damage through mitophagy enhancement.

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Section: Resultsmentioning

confidence: 99%

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

et al. 2020

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“…ATP is generated in the cells by mitochondria, which are known as the powerhouse of the cell, through the OXPHOS system. The energy supply is critical for the ATP-dependent neurotransmission in the nervous system, including the auditory system [ 16 ]. The function and morphology of the mitochondria decline with aging, which results in an energy deficit and age-dependent decline in organ function [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mitophagy serves as a major quality control mechanism to remove aged and impaired mitochondria in neurons [ 16 ]. The disruption of mitophagy has been associated with various neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Hearing Loss in C57BL/6J Mice Is Associated with Mitophagy Impairment in the Central Auditory System

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Jun

et al. 2020

IJMS

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Aging is associated with functional and morphological changes in the sensory organs, including the auditory system. Mitophagy, a process that regulates the turnover of dysfunctional mitochondria, is impaired with aging. This study aimed to investigate the effect of aging on mitophagy in the central auditory system using an age-related hearing loss mouse model. C57BL/6J mice were divided into the following four groups based on age: 1-, 6-, 12-, and 18-month groups. The hearing ability was evaluated by measuring the auditory brainstem response (ABR) thresholds. The mitochondrial DNA damage level and the expression of mitophagy-related genes, and proteins were investigated by real-time polymerase chain reaction and Western blot analyses. The colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus was analyzed by immunofluorescence analysis. The expression of genes involved in mitophagy, such as PINK1, Parkin, and BNIP3 in the mouse auditory cortex and inferior colliculus, was investigated by immunohistochemical staining. The ABR threshold increased with aging. In addition to the mitochondrial DNA integrity, the mRNA levels of PINK1, Parkin, NIX, and BNIP3, as well as the protein levels of PINK1, Parkin, BNIP3, COX4, LC3B, mitochondrial oxidative phosphorylation (OXPHOS) subunits I–IV in the mouse auditory cortex significantly decreased with aging. The immunofluorescence analysis revealed that the colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus decreased with aging. The immunohistochemical analysis revealed that the expression of PINK1, Parkin, and BNIP3 decreased in the mouse auditory cortex and inferior colliculus with aging. These findings indicate that aging-associated impaired mitophagy may contribute to the cellular changes observed in an aged central auditory system, which result in age-related hearing loss. Thus, the induction of mitophagy can be a potential therapeutic strategy for age-related hearing loss.

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“…Due to their peerless properties as postmitotic-differentiated cells, neurons are strongly dependent on the controlled clearance of impaired proteins and organelles. Efficient removal of aggregated proteins during the aging of the neurons and dysfunctional or aged organelles is essential to prevent elevated cellular stress and neurodegenerative mechanisms [ 97 , 100 ]. A decline in mitophagy impacts mitostasis and may lead to a deficient function of the postmitotic neuron and further to cell death [ 42 ].…”

Section: Autophagy and Mitophagy As A Crucial Cellular Mechanism Pmentioning

confidence: 99%

Dietary Mitophagy Enhancer: A Strategy for Healthy Brain Aging?

2020

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Recently, nutritional interventions have received attention as promising approaches to promote human health during a lifespan. The Mediterranean and Okinawan diets have been associated with longevity and decreasing risk for age-related diseases in contrast to the Western diet. The effect might be due to several antioxidative bioactive compounds highly consumed in both diets, namely, resveratrol, hydroxytyrosol, oleuropein, curcumin, and spermidine. This review aims to address the underlying mechanisms of these compounds to enhance mental fitness throughout life with a focus on brain mitophagy. Mitophagy is the autophagic clearance of dysfunctional, redundant, and aged mitochondria. In aging and neurodegenerative disorders, mitophagy is crucial to preserve the autophagy mechanism of the whole cell, especially during oxidative stress. Growing evidence indicates that curcumin, astaxanthin, resveratrol, hydroxytyrosol, oleuropein, and spermidine might exert protective functions via antioxidative properties and as well the enhanced induction of mitophagy mediators. The compounds seem to upregulate mitophagy and thereby alleviate the clearance of dysfunctional and aged mitochondria as well as mitogenesis. Thus, the Mediterranean or Okinawan diet could represent a feasible nutritional approach to reduce the risk of developing age-related cognitive impairment and corresponding disorders via the stimulation of mitophagy and thereby ensure a balanced redox state of brain cells.

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Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cited by 182 publications

References 260 publications

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

Age-Related Hearing Loss in C57BL/6J Mice Is Associated with Mitophagy Impairment in the Central Auditory System

Dietary Mitophagy Enhancer: A Strategy for Healthy Brain Aging?

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