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Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2013 Oct 01; Vol. 22 (19), pp. 3931-46. Date of Electronic Publication: 2013 Jun 04. - Publication Year :
- 2013
-
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.
- Subjects :
- AMP-Activated Protein Kinases genetics
AMP-Activated Protein Kinases metabolism
Aged
Aged, 80 and over
Carrier Proteins genetics
Carrier Proteins metabolism
Case-Control Studies
Cell Line
DNA, Mitochondrial metabolism
Energy Metabolism
Humans
Hybrid Cells metabolism
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Middle Aged
Mitochondria enzymology
Mitochondria genetics
Mitochondrial Dynamics
Oxygen Consumption
RNA-Binding Proteins
Sirtuin 1 genetics
Sirtuin 1 metabolism
TOR Serine-Threonine Kinases genetics
TOR Serine-Threonine Kinases metabolism
Alzheimer Disease metabolism
Cognitive Dysfunction metabolism
Mitochondria physiology
Mitochondria ultrastructure
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 22
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23740939
- Full Text :
- https://doi.org/10.1093/hmg/ddt247