Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture

• Published in: Neurobiology of disease Vol. 15; no. 1; pp. 29 - 39
• Main Authors: Trimmer, Patricia A., Keeney, Paula M., Borland, M.Kate, Simon, Frederic A., Almeida, Jatanna, Swerdlow, Russell H., Parks, Janice P., Parker, W.Davis, Bennett, James P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004; Elsevier
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Bioenergetic phenotype; Cell Line; Cybrids; DNA Replication - physiology; DNA, Mitochondrial - biosynthesis; Electron Transport Complex IV - metabolism; Energy Metabolism - physiology; Gene Expression Regulation - physiology; Humans; Hybrid Cells - metabolism; Hybrid Cells - pathology; Hybrid Cells - ultrastructure; Inclusion Bodies - genetics; Inclusion Bodies - metabolism; Inclusion Bodies - pathology; Intracellular Membranes - metabolism; Intracellular Membranes - pathology; Intracellular Membranes - ultrastructure; Microscopy, Electron; Middle Aged; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - ultrastructure; Models, Biological; mtDNA; Replicative advantage; Cybrids; Replicative advantage; mtDNA; Bioenergetic phenotype; Alzheimer's disease
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2003.09.011

We created and studied new cybrid cell lines from sporadic Alzheimer's disease (SAD) or control (CTL) subjects to assess mitochondrial abnormalities just after metabolic selection (“early passage”) and again six passages later (“late passage”). Cytochrome oxidase (CO) activities in early passage SAD cybrids created independently from the same platelet samples were highly correlated. Early passage SAD and CTL cybrids showed equivalent mitochondrial morphologies. Late passage SAD cybrids showed increased mitochondrial number, reduced mitochondrial size, and an approximately eightfold increase in morphologically abnormal mitochondria. Deficiency of SAD cybrid mitochondrial membrane potentials (Δ Ψ M) increased with passage. Mitochondrial bromodeoxyuridine (BrdU) uptake to estimate mitochondrial DNA (mtDNA) synthesis did not change with passage in CTL but increased in SAD cybrids. With time in culture, SAD mtDNA appears to replicate faster in cybrids, yielding cells with relative worsening of bioenergetic function. Metabolically deleterious SAD mitochondrial genes, like those in yeast, may have a replicative advantage over nondeleterious mitochondrial genes that assume dominance in CTL cybrids.