Presynapses are mitophagy pit stops that prevent axon degeneration

Defects in neuronal mitophagy have been linked to neurodegenerative diseases including Parkinson's disease. However, despite the importance of mitophagy in neuronal homeostasis, the mechanistic basis for neurodegeneration when mitophagy is defective is unclear. Here, using human neurons, we discover that presynapses are mitophagy pit stops for damaged axonal mitochondria. We show that while mitochondrial damage and PINK1/Parkin activation events are distributed throughout axons, mitophagy initiation and autophagosome formation are restricted to presynapses, which we show contain the machineries required for mitophagy. Being the primary sites of axonal mitophagy, presynapses were vulnerable when PINK1/Parkin mitophagy was defective. We observed local cytochrome c release within presynapses from an accumulation of damaged mitochondria. This resulted in downstream degradative caspase activation, defining a mechanism for neurodegeneration. Pharmacological rescue of axon degeneration was achieved through synthetic upregulation of receptor mediated mitophagy with the clinically approved compound Roxadustat, revealing a potential therapeutic avenue for disease.