Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines
Open accessAbstract
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.
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AD and MCI cybrid lines showed reduced basal oxygen consumption, suggesting reduced respiratory flux.
“The AD and MCI lines showed reduced basal oxygen consumption, which suggests reduced respiratory flux.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [93]
MCI cybrid lines generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells showed low mean COX activity and other downstream molecular changes.
“Two studies in which “MCI cybrid” lines were generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells observed low mean COX activity and other downstream molecular changes [92, 93].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [93]
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References 84 · Cited by 133
- Authors
- Silva, D. F., Selfridge, J. E., Lu, J., E, L., Roy, N., Hutfles, L., Burns, J. M., Michaelis, E. K., Yan, S., Cardoso, S. M., & Swerdlow, R. H.
- Affiliations
- University of Kansas (US)
- University of Coimbra (PT)
- Corresponding author
- Swerdlow, R. H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-06-04
- Volume
- 22
- Issue
- 19
- Pages
- 3931-3946
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3888119
- OpenAlex
- W2119278281
- Cited by
- 133
- References
- 84
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 10 · 2021: 15 · 2020: 19 · 2019: 13 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 7 · 2014: 7 · 2013: 6
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Morgan Family Foundation
- Fundação para a Ciência e a Tecnologia
- National Institute on Aging (P30AG035982)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Alzheimer's disease, mild cognitive impairment, bioenergetic dysfunction, mitochondrial dysfunction, mitochondrial transfer, platelet mitochondria, SH-SY5Y cells, mitochondrial mass, mitochondrial fission and fusion, oxygen consumption, respiratory coupling, glucose utilization, ATP/ADP ratio, NAD+/NADH ratio, HIF-1α, PGC-1α, SIRT1, AMPK, p38 MAPK, mTOR, retrograde signaling
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Carrier Proteins, Cell Line, DNA, Mitochondrial, Energy Metabolism, Humans, Hybrid Cells, Middle Aged, Mitochondria, Oxygen Consumption, Case-Control Studies, RNA-Binding Proteins, Reactive Oxygen Species, Hypoxia-Inducible Factor 1, alpha Subunit, AMP-Activated Protein Kinases, Sirtuin 1, TOR Serine-Threonine Kinases, Cognitive Dysfunction, Mitochondrial Dynamics
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