Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. Hum Mol Genet 2013 Oct 01;22(19):3931-46
Date
06/07/2013Pubmed ID
23740939Pubmed Central ID
PMC3888119DOI
10.1093/hmg/ddt247Scopus ID
2-s2.0-84888799219 (requires institutional sign-in at Scopus site) 105 CitationsAbstract
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.
Author List
Silva DF, Selfridge JE, Lu J, E L, Roy N, Hutfles L, Burns JM, Michaelis EK, Yan S, Cardoso SM, Swerdlow RHAuthor
Lezi E PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAged
Aged, 80 and over
Alzheimer Disease
Carrier Proteins
Case-Control Studies
Cell Line
Cognitive Dysfunction
DNA, Mitochondrial
Energy Metabolism
Humans
Hybrid Cells
Hypoxia-Inducible Factor 1, alpha Subunit
Middle Aged
Mitochondria
Mitochondrial Dynamics
Oxygen Consumption
RNA-Binding Proteins
Reactive Oxygen Species
Sirtuin 1
TOR Serine-Threonine Kinases
