Cited by 249Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsCalcium signaling and nucleotide metabolism

Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease

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Sheehan, Jason P., Swerdlow, Russel H., Miller, Scott W., Davis, Robert E., Parks, Jan K., Parker, W. Davis, Tuttle, Jeremy B.·1997·The Journal of Neuroscience

Abstract

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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Crossref · 10.1523/jneurosci.17-12-04612.1997

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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
Published
1997-06-15
Volume
17
Issue
12
Pages
4612-4622
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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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