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Cited by 22Alzheimer's disease research and treatmentsMitochondrial Function and PathologyParkinson's Disease Mechanisms and Treatments

PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer’s Disease Trans-Mitochondrial Cybrid Cells

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Du, Fang, Yu, Qing, Yan, Shirley ShiDu·2021·Journal of Alzheimer's Disease
DOI 10.3233/jad-210095PMC PMC9004622
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Abstract

Background: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer’s disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice. Objective: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction. Methods: Using trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions. Results: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuates mitochondrial defects and rescues neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for the clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation. Conclusion: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.

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  • Downregulation of PINK1 and PRKN in Alzheimer's disease results in persistence of dysfunctional, ROS-generating mitochondria.

    “genes such as PINK1 (encoding for PTEN-induced kinase 1) and PRKN (encoding for 465-amino acid residue E3 ubiquitin ligase), which regulate mitochondrial quality control, are downregulated in AD, resulting in the persistence of dysfunctional, ROS-generating mitochondria [143].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [143]

    The Discussion (page unavailable) reports reduced PINK1 in AD-affected brains and AD cybrid cells and says insufficient clearance allows dysfunctional mitochondria to persist. The Results (page unavailable) report elevated ROS in AD cybrids that fell with PINK1 activation. The paper does not report PRKN downregulation in AD, so the claim about both genes is not fully supported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PINK1 and PRKN are downregulated in Alzheimer's disease.

    “genes such as PINK1 (encoding for PTEN-induced kinase 1) and PRKN (encoding for 465-amino acid residue E3 ubiquitin ligase), which regulate mitochondrial quality control, are downregulated in AD, resulting in the persistence of dysfunctional, ROS-generating mitochondria [143].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [143]

    The Results section, “Decreased PINK1 level in the differentiated AD cybrid cells” (page unavailable), reports 50–60% lower PINK1 expression in AD cybrids than in non-AD cells. The paper does not report that PRKN is downregulated in AD, so the claim is supported for PINK1 but not PRKN. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mitophagy failure is emerging as a central theme in Alzheimer's disease.

    “Furthermore, mitophagy failure is emerging as a central theme, whereby genes such as PINK1 (encoding for PTEN-induced kinase 1) and PRKN (encoding for 465-amino acid residue E3 ubiquitin ligase), which regulate mitochondrial quality control, are downregulated in AD, resulting in the persistence of dysfunctional, ROS-generating mitochondria [143].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [143]

    The Discussion (page not provided) describes insufficient clearance of defective mitochondria in AD and says PINK1-mediated mitophagy helps eliminate them. The Results report reduced PINK1 expression in AD cybrid cells and elevated ROS, but the paper does not establish that PRKN is also downregulated in AD. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Du, F., Yu, Q., & Yan, S. S.
Affiliations
Columbia University (US)
Corresponding author
Yan, Shirley ShiDu
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2021-06-15
Volume
81
Issue
4
Pages
1749-1761
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-210095
PMC
PMC9004622
OpenAlex
W3160218209
Cited by
22
References
4
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 6
FWCI
2.29
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R37AG037319, RF1AG054320, R01AG053041, R01AG069426, R01AG044793, R56AG064934, P30AG035982)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
PINK1, Alzheimer's disease
MeSH terms
PTEN-Induced Putative Kinase, Alzheimer Disease, Autophagy, Cell Differentiation, Humans, Mitochondria, Neurons, Phosphorylation, Protein Kinases, Synapses, Mitophagy

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