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Review
. 2017:146:259-302.
doi: 10.1016/bs.pmbts.2016.12.017. Epub 2017 Feb 1.

Mitochondria, Cybrids, Aging, and Alzheimer's Disease

R H Swerdlow  1 , S Koppel  2 , I Weidling  2 , C Hayley  2 , Y Ji  2 , H M Wilkins  2
Affiliations
Review

Mitochondria, Cybrids, Aging, and Alzheimer's Disease

R H Swerdlow et al. Prog Mol Biol Transl Sci. 2017.

Abstract

Mitochondrial and bioenergetic function change with advancing age and may drive aging phenotypes. Mitochondrial and bioenergetic changes are also documented in various age-related neurodegenerative diseases, including Alzheimer's disease (AD). In some instances AD mitochondrial and bioenergetic changes are reminiscent of those observed with advancing age but are greater in magnitude. Mitochondrial and bioenergetic dysfunction could, therefore, link neurodegeneration to brain aging. Interestingly, mitochondrial defects in AD patients are not brain-limited, and mitochondrial function can be linked to classic AD histologic changes including amyloid precursor protein processing to beta amyloid. Also, transferring mitochondria from AD subjects to cell lines depleted of endogenous mitochondrial DNA (mtDNA) creates cytoplasmic hybrid (cybrid) cell lines that recapitulate specific biochemical, molecular, and histologic AD features. Such findings have led to the formulation of a "mitochondrial cascade hypothesis" that places mitochondrial dysfunction at the apex of the AD pathology pyramid. Data pertinent to this premise are reviewed.

Keywords: Aging; Alzheimer's disease; Bioenergetics cybrids; Mitochondria.

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Figures

Figure 1
Figure 1. Oxidation-mediated mtDNA mutation
(A) A G-C pair is converted to a T-A pair following the oxidative deamination of a cytosine nucleotide to a uracil nucleotide. (B) A G-C-pair is converted to a T-A pair following the oxidative conversion of a guanosine to 8-hydroxy-2-deoxy guanosine and then to 8-oxo-2-deoxyguanosine.
Figure 2
Figure 2. Fluorodeoxyglucose positron emission tomography (FDG PET) scan from an AD patient
In the normal case the cortical region should show a consistent level of relatively high glucose uptake and, therefore, utilization. In in this FDG PET scan from an individual with AD there is attenuation of the high cortical glucose uptake/utilization signal (indicated by a red-orange color) in the region of the posterior temporal/inferior parietal cortical regions (indicated by a yellow-green color).
Figure 3
Figure 3. The cybrid technique
A cell line’s endogenous mtDNA is removed to create a ρ0 cell line, which lacks respiratory-competence and must be maintained in medium supplemented with pyruvate and uridine. After mixing ρ0 cells with mitochondria-containing cytoplasts or platelets, and facilitating cytosolic mixing by addition of detergent, some ρ0 cells incorporate exogenous mitochondria and by extension their mtDNA. The transferred mtDNA allows for the restoration of respiratory competence, and the newly created cybrid cells can be selected for by removing pyruvate and uridine from the medium (leading to the removal of residual untransformed ρ0 cells). The cybrid cells that result from a single fusion can be grown as separate clonal colonies; in cases where the donor mtDNA carries a heteroplasmic mutation, the individual cybrid clonal lines can be analyzed to address issues of threshold. Alternatively, the cybrid cells that result from a single fusion can be expanded together, creating a single cybrid line that can be compared to other unique cybrid cell lines.
Figure 4
Figure 4. The AD mitochondrial cascade hypothesis
Inheritance from both parents determine an individual’s bioenergetic set-point and durability, with the mother having the greater input due to her contribution of the mtDNA. Over time mitochondrial efficiency declines, likely due to accumulating damage to the mtDNA. At relatively low levels it is possible to compensate for this change (compensated brain aging), although the compensatory process may itself have consequences. More profound declines in mitochondria function, which may occur as further damage accumulates, can lead to a stage of uncompensated brain aging, which associates with other consequences as well as symptomatic AD.
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