Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains
Open accessAbstract
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 AD mouse 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.
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Other studies have demonstrated impaired mitophagy and parkin accumulation in AD neurons.
“other studies have demonstrated impaired mitophagy and parkin accumulation in AD neurons45,46.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [46]
The Discussion reports inadequate capacity to clear damaged mitochondria despite enhanced induction of mitophagy, so the unqualified phrase “impaired mitophagy” misses that distinction. The section on increased Parkin translocation reports greater recruitment of Parkin to depolarized mitochondria in AD neurons, not overall Parkin accumulation; the patient-brain results instead report declining Parkin levels. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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- Authors
- Ye, X., Sun, X., Starovoytov, V., & Cai, Q.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Cai, Qian
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-12
- Volume
- 24
- Issue
- 10
- Pages
- 2938-2951
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4406302
- OpenAlex
- W2151283457
- Cited by
- 274
- References
- 15
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 24 · 2023: 22 · 2022: 40 · 2021: 45 · 2020: 41 · 2019: 13 · 2018: 17 · 2017: 15 · 2016: 12 · 2015: 6
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institute on Aging (R00AG033658)
- National Institute of Neurological Disorders and Stroke (R01NS089737)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Parkin, mitophagy, Alzheimer's disease, amyloid precursor protein, mitochondrial quality control, mitochondrial depolarization, mitochondrial stress
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Mutation, Neurons, Amyloid beta-Protein Precursor, Ubiquitin-Protein Ligases, Mice, Mitophagy
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