Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to rho0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4, 5-triphosphate (InsP3)-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. beta-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.
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Mean COX activity was lower in cybrid lines containing AD subject mtDNA than in cybrid lines containing control subject mtDNA.
“Mean COX activity was lower in cybrid lines containing AD subject mtDNA than it was in cybrid lines containing control subject mtDNA [90, 91].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [90]
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Synaptic Energy Use and Supply
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“We isolated platelets from AD and age-matched control subjects and fused those platelets with both human neuroblastoma SH-SY5Y cells and human NT2 teratocarcinoma cells depleted of their endogenous mtDNA [24,25].”
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Is mitochondrial DNA depletion involved in Alzheimer's disease?
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Self-citationDifferential alterations in antioxidant capacity in cells from Alzheimer patients
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Self-citationMitochondrial Function and Neurodegenerative Diseases
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Self-citation
- Authors
- Sheehan, J. P., Swerdlow, R. H., Miller, S. W., Davis, R. E., Parks, J. K., Parker, W. D., & Tuttle, J. B.
- Affiliations
- Neurological Surgery (US)
- University of Virginia (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1997-06-15
- Volume
- 17
- Issue
- 12
- Pages
- 4612-4622
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6573324
- OpenAlex
- W1532873251
- Cited by
- 249
- References
- 118
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 8
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- sporadic Alzheimer's disease, mitochondrial dysfunction, cybrids, calcium homeostasis, reactive oxygen species, mitochondrial DNA depletion, intracellular calcium, IP3 receptor, mitochondrial calcium buffering, amyloid-beta, nerve growth factor, succinic acid, carbachol, SH-SY5Y cells, platelet mitochondria
- MeSH terms
- Adenine Nucleotides, Aged, Alzheimer Disease, Blood Platelets, Calcium, Electron Transport Complex IV, Cytosol, DNA, Mitochondrial, Electron Transport, Female, Homeostasis, Humans, Kinetics, Male, Membrane Fusion, Middle Aged, Mitochondria, Multienzyme Complexes, Neuroblastoma, Oxidoreductases, Reference Values, Succinate Dehydrogenase, Tumor Cells, Cultured, NAD(P)H Dehydrogenase (Quinone), Reactive Oxygen Species, Electron Transport Complex II
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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