Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

Zeng, Kuan; Yu, Xuan; Mahaman, Yacoubou Abdoul Razak; Wang, Jian‐Zhi; Liu, Rong; Li, Yang; Wang, Xiaochuan

doi:10.1186/s40035-022-00305-1

Cited by 20 publications

(17 citation statements)

References 118 publications

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“…Since mitophagy integrity is important in maintaining neural function, we examined mitophagic flux. We found that C. elegans treated with olanzapine had a low mitophagic flux, supporting the idea that neural lesion is associated with mitophagy deficits (Zeng et al., 2022). Together, these results highlight that defective mitophagy may contribute to neuronal deficits, leading to cognitive decline.…”

Section: Discussionsupporting

confidence: 87%

Impaired mitophagosome–lysosome fusion mediates olanzapine‐induced aging

Chen,

Wang,

Zheng

et al. 2023

Aging Cell

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The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine‐induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD‐induced adverse effects associated with accelerated aging.

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Section: Discussionsupporting

confidence: 87%

Impaired mitophagosome–lysosome fusion mediates olanzapine‐induced aging

Chen,

Wang,

Zheng

et al. 2023

Aging Cell

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“…In Alzheimer's disease, Aβ1‐40 induced pericyte mitophagy through the PINK1/Parkin pathway 52 . Under physiological conditions, PINK1 is transported to the inner mitochondrial membrane (IMM) and degraded by presenilin‐associated rhomboid‐like protease (PARL) 53 . However, in damaged mitochondria, the degradation of PINK1 is inhibited to maintain PINK1 present on the outer mitochondrial membrane (OMM) 54 .…”

Section: Discussionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

et al. 2023

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Aims: Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. Methods:We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. Results:We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/ Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown.Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. Conclusion:Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.

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“…Our KEGG pathway enrichment analysis showed that autophagy, mitophagy, and metabolic pathways are the most affected in both UNC93A and WDR27 inhibitory conditions. Interestingly, these pathways play an important role in Aβ clearance, and thus dysfunction may lead to the development of Alzheimer’s disease ( Zeng et al, 2022 ). As reduced autophagy activity was related to increased cell death in response to intracellular stress ( Galati et al, 2019 ), these variants could have a negative effect on BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family

Alvarez

Aguilar-Pineda

Ortiz-Manrique

et al. 2023

Front. Mol. Neurosci.

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Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer’s disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (UNC93A: rs7739897 and WDR27: rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family. In silico and in vitro studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.

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Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

Cited by 20 publications

References 118 publications

Impaired mitophagosome–lysosome fusion mediates olanzapine‐induced aging

Impaired mitophagosome–lysosome fusion mediates olanzapine‐induced aging

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family

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