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Cited by 341Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients

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Wang, Xinglong, Su, Bo, Fujioka, Hisashi, Zhu, Xiongwei·2008·The American Journal of Pathology
DOI 10.2353/ajpath.2008.071208PMC PMC2475784
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Abstract

Mitochondrial function relies heavily on its morphology and distribution, alterations of which have been increasingly implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). In this study, we found abnormal mitochondrial distribution characterized by elongated mitochondria that accumulated in perinuclear areas in 19.3% of sporadic AD (sAD) fibroblasts, which was in marked contrast to their normally even cytoplasmic distribution in the majority of human fibroblasts from normal subjects (>95%). Interestingly, levels of dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution, were decreased significantly in sAD fibroblasts. To explore the potential role of DLP1 in mediating mitochondrial abnormalities in sAD fibroblasts, both the overexpression of a dominant negative DLP1 mutant and the reduced expression of DLP1 by miR RNAi in human fibroblasts from normal subjects significantly increased mitochondrial abnormalities. Moreover, overexpression of wild-type DLP1 in sAD fibroblasts rescued these mitochondrial abnormalities. Based on these data, we conclude that DLP1 reduction causes mitochondrial abnormalities in sAD fibroblasts. We further demonstrate that elevated oxidative stress and increased amyloid beta production are likely the potential pathogenic factors that cause DLP1 reduction and abnormal mitochondrial distribution in AD cells.

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  • MFN1, MFN2, OPA1, and FIS1 levels were decreased in the brains and neurons of AD patients and APOE4 carriers.

    “MFN1, MFN2, OPA1, and FIS1 levels were decreased in the brains and neurons of AD patients and APOE4 carriers [37,38], whereas APOE4 N2A cells expressed higher levels of fission and fusion proteins than APOE3 N2A cells [33].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [37]

    The “DLP1 Level Change in sAD Fibroblasts” section reports reduced DLP1 but no significant change in OPA1 in fibroblasts. Our copy does not report MFN1, MFN2, OPA1, or FIS1 levels in AD brains or neurons or in APOE4 carriers (searched for the named proteins, brain, neurons, and APOE4). The fibroblast result does not establish or contradict the claimed findings in those other populations. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • APOE-dependent alterations in mitochondrial fusion/fission protein levels have been shown in other studies; however, those were contradictory.

    “In contrast, APOE-dependent alterations in mitochondrial fusion/fission protein levels have been shown in other studies; however, those were contradictory.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [37]

    The section on wild-type and Swedish-mutant APP reports reduced DLP1 levels after APP overexpression, not APOE-dependent changes. The passages on mitochondrial fission and fusion do not report contradictory findings from other studies. Searches for APOE-dependent effects and apolipoprotein E genotype found no passage addressing either part of the claim. (LLM, conf=0.76)

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Cited by

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Authors
Wang, X., Su, B., Fujioka, H., & Zhu, X.
Affiliations
Case Western Reserve University (US)
Corresponding author
Zhu, Xiongwei
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2008-08
Volume
173
Issue
2
Pages
470-482
ISSN
0002-9440 (ISSN-L)
DOI
10.2353/ajpath.2008.071208
PMC
PMC2475784
OpenAlex
W1989167108
Cited by
341
References
4
Citations by year
2026: 4 · 2025: 13 · 2024: 19 · 2023: 15 · 2022: 17 · 2021: 18 · 2020: 22 · 2019: 21 · 2018: 21 · 2017: 19 · 2016: 24 · 2015: 14 · 2014: 10 · 2013: 16 · 2012: 26
FWCI
10.26
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association (IIRG-07-60196)
  • National Institutes of Health (AG031852)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Drp1, sporadic Alzheimer's disease, mitochondrial morphology, mitochondrial distribution, mitochondrial fission, fibroblasts, oxidative stress, amyloid-beta, dominant-negative mutant, RNAi knockdown
MeSH terms
Aged, Alzheimer Disease, Cells, Cultured, Female, Fibroblasts, Humans, Male, Microtubule-Associated Proteins, Mitochondria, Amyloid beta-Peptides, Oxidative Stress, GTP Phosphohydrolases, Mitochondrial Proteins, Dynamins, Microscopy, Electron, Transmission

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