Dataset Information

Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains.

ABSTRACT: Accumulation of dysfunctional mitochondria is one of the hallmarks in Alzheimer's disease (AD). Mitophagy, a selective autophagy for eliminating damaged mitochondria, constitutes a key cellular pathway in mitochondrial quality control. Recent studies established that acute depolarization of mitochondrial membrane potential (??m) using ??m dissipation reagents in vitro induces Parkin-mediated mitophagy in many non-neuronal cell types or neuronal cell lines. However, neuronal pathways inducing mitophagy, particularly under pathophysiological relevant context in AD mouse models and patient brains, are largely unknown. Here, we reveal, for the first time, that Parkin-mediated mitophagy is robustly induced in mutant hAPP neurons and AD patient brains. In the absence of ??m dissipation reagents, hAPP neurons exhibit increased recruitment of cytosolic Parkin to depolarized mitochondria. Under AD-linked pathophysiological conditions, Parkin translocation predominantly occurs in the somatodendritic regions; such distribution is associated with reduced anterograde and increased retrograde transport of axonal mitochondria. Enhanced mitophagy was further confirmed in AD patient brains, accompanied with depletion of cytosolic Parkin over disease progression. Thus, aberrant accumulation of dysfunctional mitochondria in AD-affected neurons is likely attributable to inadequate mitophagy capacity in eliminating increased numbers of damaged mitochondria. Altogether, our study provides the first line of evidence that AD-linked chronic mitochondrial stress under in vitro and in vivo pathophysiological conditions effectively triggers Parkin-dependent mitophagy, thus establishing a foundation for further investigations into cellular pathways in regulating mitophagy to ameliorate mitochondrial pathology in AD.

SUBMITTER: Ye X

PROVIDER: S-EPMC4406302 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains.

Ye Xuan X Sun Xiaqin X Starovoytov Valentin V Cai Qian Q

Human molecular genetics 20150212 10

Accumulation of dysfunctional mitochondria is one of the hallmarks in Alzheimer's disease (AD). Mitophagy, a selective autophagy for eliminating damaged mitochondria, constitutes a key cellular pathway in mitochondrial quality control. Recent studies established that acute depolarization of mitochondrial membrane potential (Δψm) using Δψm dissipation reagents in vitro induces Parkin-mediated mitophagy in many non-neuronal cell types or neuronal cell lines. However, neuronal pathways inducing mit ...[more]

PMID: 25678552

Similar Datasets

Project description:Mutations in PRKN are the most common cause of early onset Parkinson's disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in PRKN mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from PRKN mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Fibroblasts from 4 controls and 4 PRKN mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Direct conversion of control and PRKN mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

Project description:MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-Ⅱ protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria. [BMB Reports 2022; 55(7): 354-359].

Dataset Information

Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains.

Publications

Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets