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Neurons are metabolically active cells with high-energy demands at locations distant from the cell body and are particularly dependent on mitochondrial function. Mitochondria are essential organelles for neuronal function and survival. Mitochondrial damage has emerged as a central concern in major neurodegenerative diseases, including the devastating Alzheimer's disease (AD). Damaged mitochondria not only produce energy less efficiently but also release harmful reactive oxygen species and initiate apoptotic cascades. Thus, efficient elimination of damaged mitochondria is critical for the maintenance of mitochondrial homeostasis and neuronal health. While elaborative systems have been proposed to ensure mitochondrial integrity and function in neurons (Sheng and Cai, Nature Review Neuroscience 2012), mitophagy, a cargo-selective autophagy for the removal of damaged mitochondria, constitutes the key quality control mechanism of mitochondria involving sequestration of damaged mitochondria within autophagosomes for subsequent lysosomal degradation. Using long time-lapse confocal imaging in live primary cortical neurons, our documented work has revealed unique features of mitophagy in healthy and diseased neurons (Cai et al., Current Biology 2012; Cai et al., Autophagy 2012; Ye et al., Human Molecular Genetics 2015; Tammineni et al., Human Molecular Genetics 2017; Han et al., EMBO Reports 2020; Han et al., Autophagy 2020). Mitochondrial pathology—abnormal accumulation of damaged mitochondria is a hallmark in AD patient brains. However, the underlying mechanism of mitochondrial quality control in AD is still poorly understood. Mounting evidence is now highlighting a pivotal role of mitochondrial dysfunction in the development of AD pathologies. The research objective of this study is to determine how mitophagy is regulated in AD neurons and to address whether mitophagy failure participates in the early pathophysiology of AD.
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