title: Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines.
abstract: Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD+/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1α, PGC1α, SIRT1, AMPK, p38 MAPK and mTOR. Several endpoints suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission-fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Silva
authors.forename: J Eva
authors.initials: JE
authors.lastname: Selfridge
authors.forename: Jianghua
authors.initials: J
authors.lastname: Lu
authors.forename: Lezi
authors.initials: L
authors.lastname: E
authors.forename: Nairita
authors.initials: N
authors.lastname: Roy
authors.forename: Lewis
authors.initials: L
authors.lastname: Hutfles
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Burns
authors.forename: Elias K
authors.initials: EK
authors.lastname: Michaelis
authors.forename: ShiDu
authors.initials: S
authors.lastname: Yan
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D060825:Cognitive Dysfunction / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure*; D063154:Mitochondrial Dynamics; D010101:Oxygen Consumption; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1