Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture.
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 (DeltaPsi(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.
Trimmer
Patricia A
PA
Center for the Study of Neurodegenerative Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Keeney
Paula M
PM
Borland
M Kate
MK
Simon
Frederic A
FA
Almeida
Jatanna
J
Swerdlow
Russell H
RH
Parks
Janice P
JP
Parker
W Davis
WD
Bennett
James P
JP
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004261:DNA Replication / Q000502:physiology; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007425:Intracellular Membranes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008954:Models, Biological
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV