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Damaged mitochondria are removed from the cell in a process termed mitophagy. This pathway is likely to be important for neuronal homeostasis, as mutations in pathway components cause Parkinson’s disease and ALS. We used live imaging to investigate the spatiotemporal dynamics of mitophagy in primary neurons following mild oxidative stress. Mitophagy-associated proteins, including Parkin, TBK1, and OPTN rapidly translocate to depolarized mitochondria and damaged organelles were efficiently sequestered within autophagosomes within an hour of damage. Surprisingly, the downstream degradation of engulfed mitochondria was delayed, primarily due to the slow acidification of the resulting mitophagosomes. Expression of an ALS-associated mutation in OPTN was sufficient to disrupt mitochondrial network function and mild oxidative stress further exacerbated this effect. These results suggest that slow turnover of damaged mitochondria may increase neuronal susceptibility to neurodegeneration.

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