QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (119) Citing Articles via Google Scholar Google Scholar Articles by Sheehan, J. P. Articles by Tuttle, J. B. Search for Related Content PubMed PubMed Citation Articles by Sheehan, J. P. Articles by Tuttle, J. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Alzheimer's Disease Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL

 Previous Article  |  Next Article 

Volume 17, Number 12, Issue of June 15, 1997 pp. 4612-4622
Copyright ©1997 Society for Neuroscience

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer's Disease

Received Jan. 15, 1997; revised March 5, 1997; accepted April 2, 1997.

Jason P. Sheehan¹, Russel H. Swerdlow⁴, Scott W. Miller⁵, Robert E. Davis⁵, Jan K. Parks⁴, W. Davis Parker⁴, and Jeremy B. Tuttle^{2, 3}

Departments of ¹ Neurological Surgery, ² Neuroscience, ³ Urology, and ⁴ Neurology, University of Virginia, Charlottesville, Virginia 22908, and ⁵ MitoKor Corporation, San Diego, California 92121

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 ⁰ 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. -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.

Key words: Alzheimer's disease; mitochondria; calcium; neurodegeneration; reactive oxygen species; nerve growth factor; -amyloid

This article has been cited by other articles:

				Z. Yuan, T. Miyoshi, Y. Bao, J. P. Sheehan, A. H. Matsumoto, and W. Shi Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1336 - H1343. [Abstract] [Full Text] [PDF]

				X. Wang, B. Su, H. Fujioka, and X. Zhu Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients Am. J. Pathol., August 1, 2008; 173(2): 470 - 482. [Abstract] [Full Text] [PDF]

				S. M. Khan, R. M. Smigrodzki, and R. H. Swerdlow Cell and animal models of mtDNA biology: progress and prospects Am J Physiol Cell Physiol, February 1, 2007; 292(2): C658 - C669. [Abstract] [Full Text] [PDF]

				M. Kubota, T. Kasahara, T. Nakamura, M. Ishiwata, T. Miyauchi, and T. Kato Abnormal Ca2+ Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects. J. Neurosci., November 22, 2006; 26(47): 12314 - 12324. [Abstract] [Full Text] [PDF]

				R. Li, L. Yang, K. Lindholm, Y. Konishi, X. Yue, H. Hampel, D. Zhang, and Y. Shen Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-{beta} Protein-Induced Neuron Death J. Neurosci., February 18, 2004; 24(7): 1760 - 1771. [Abstract] [Full Text] [PDF]

				A. Y. Abramov, L. Canevari, and M. R. Duchen {beta}-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase J. Neurosci., January 14, 2004; 24(2): 565 - 575. [Abstract] [Full Text] [PDF]

				G. Karthikeyan, J. H. Santos, M. A. Graziewicz, W. C. Copeland, G. Isaya, B. V. Houten, and M. A. Resnick Reduction in frataxin causes progressive accumulation of mitochondrial damage Hum. Mol. Genet., December 15, 2003; 12(24): 3331 - 3342. [Abstract] [Full Text] [PDF]

				M. A. Leissring, Y. Akbari, C. M. Fanger, M. D. Cahalan, M. P. Mattson, and F. M. LaFerla Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice J. Cell Biol., May 15, 2000; 149(4): 793 - 798. [Abstract] [Full Text] [PDF]

				D. G. Nicholls and S. L. Budd Mitochondria and Neuronal Survival Physiol Rev, January 1, 2000; 80(1): 315 - 360. [Abstract] [Full Text] [PDF]

				S. Ito, S. Ohta, K. Nishimaki, Y. Kagawa, R. Soma, S.-y. Kuno, Y. Komatsuzaki, H. Mizusawa, and J.-I. Hayashi Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer's disease PNAS, March 2, 1999; 96(5): 2099 - 2103. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help