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

Xuan Ye, Xiaqin Sun, Valentin Starovoytov, Qian Cai

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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 (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 mitophagy, particularly under pathophysiological relevant context in ADmouse 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 Δψm 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.

Original languageEnglish (US)
Article numberddv056
Pages (from-to)2938-2951
Number of pages14
JournalHuman molecular genetics
Volume24
Issue number10
DOIs
StatePublished - May 15 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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