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

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 studiesestablishedthatacutedepolarization ofmitochondrialmembranepotential(Δψm) using Δψmdissipationreagentsin vitro induces Parkin-mediated mitophagy in many non-neuronal cell types or neuronal cell lines. However, neuronal pathways inducingmitophagy, particularlyunderpathophysiologicalrelevantcontextin ADmousemodelsandpatientbrains,arelargely unknown. Here, we reveal, for the first time, that Parkin-mediated mitophagy is robustly induced in mutant hAPP neurons and AD patient brains. In theabsenceof Δψmdissipation reagents,hAPP neuronsexhibit increased recruitment of cytosolic Parkin to depolarized mitochondria. Under AD-linked pathophysiological conditions, Parkin translocation predominantly occurs in the somatodendriticregions;suchdistribution is associatedwithreducedanterograde and increasedretrogradetransport 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 studyprovidesthe firstline of evidence thatAD-linkedchronicmitochondrialstressunderin vitroandin vivopathophysiological 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.