Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer's disease

Although mitochondrial dysfunction(definition) and increased oxidative stress are found in Alzheimer's disease (AD), the origin(s) of the mitochondrial dysfunction, its causal relationship to oxidative stress and the mechanisms of their downstream effects to yield synaptic dysfunction and neuronal death are not known with certainty. The discovery of "classic" mitochondrial diseases where bioenergetic deficiencies were associated with causal mutations or deletions in mitochondrial DNA (mtDNA) generated a search for similar abnormalities in AD samples. At least three-dozen studies since 1992 have failed to find consistent mutational abnormalities in AD mtDNA beyond those associated with aging, with most studies carried out in postmortem brain. Historically, the publication of a new mutation or deletion is followed by other studies that fail to confirm the initial finding. Promising recent findings include heteroplasmic mutations in the D-loop control region. AD brain mtDNA consistently has more oxidative damage beyond that due to aging, providing the potential for generation of mutations/deletions and postgenomic problems with transcriptional regulation. To date no AD brain studies have examined individual neurons to search for clonal expansions of deleted mtDNA's like two recent reports in Parkinson's disease substantia nigra. Cybrid (cytoplasmic hybrid) models, in which mitochondrial DNA (mtDNA) from accessible tissue (platelets) of living AD patients is expressed in replicating human neural cells initially devoid of their own endogenous mtDNA (rho(0) cells) revealed that decreased cytochrome oxidase (CO) activity, increased oxidative stress, increased beta amyloid production, activation of detrimental intracellular signaling and caspases, accelerated mtDNA proliferation, and abnormal mitochondrial morphology and transport can be transmitted through expression of mtDNA from living AD patients. Carrying these cybrid observations into AD brain is necessary to demonstrate any causality of brain mtDNA to contribute to pathogenesis. A novel protein transfection technology that allows transfer of mtDNA into mitochondria of cells ("protofection") will allow this question to be examined. The contribution of altered mtDNA to pathogenesis and progression of AD is suggestive, not proven, and likely very heterogenous.