Mitochondrial DNA damage is thought to be important in aging, but not all such damage is similarly relevant to aging. For example, researchers have produced mice that generate excessive numbers of point mutations in mitochondrial DNA, and these mice appear to suffer little harm as a result (with the caveat that different groups have found different degrees of outcome in this sort of investigation). Deletion mutations, however, are a different story. Some deletions result in mitochondria that are both dysfunctional and privileged in some way, better able to replicate or evade quality control mechanisms than their peers, even while they fail to properly perform their assigned tasks. These broken mitochondria quickly take over the mitochondrial population of a cell, turning that cell into a malfunctioning exporter of damaging oxidative molecules.
Unfortunately comprehensive proof of this picture, as opposed to the existing strong indirect evidence, has yet to be assembled. That proof may or may not arrive before the development of some form of rejuvenation therapy based on prevention or repair or working around deletion mutations, such as the allotopic expression of mitochondrial genes. Such a therapy would in and of itself provide strong evidence for or against mitochondrial mutations as a cause of aging, based on whether or not it works in animal studies. For now, more indirect evidence is what we have, however, and here researchers here provide a new set of supporting evidence for the importance of mitochondrial DNA deletions in degenerative aging by comparing samples from people with and without Alzheimer's disease. On average, comparing people of the same chronological age, those suffering from later stages of age-related disease should have a higher load of the forms of cell and tissue damage that cause aging.
Research suggests that mitochondrial changes are a driving force, rather than a consequence, of the aging process and Alzheimer's disease pathogenesis. Although point mutations of mitochondrial DNA have been hypothesized as being a critical cause of aging, there is evidence that they may not be fully explanatory. Mitochondria are dynamic organelles with very short half-lives. Continuous replication of mitochondrial DNA (mtDNA) is required for assignment to new mitochondria, resulting in a significant error rate and accumulation of mutated in mtDNA genome over time and space. We hypothesized that, beyond point mutations, different types of mtDNA rearrangements should be extensively distributed in aging cells. As these rearrangements are often not detected by routine methods such as polymerase chain reaction, we applied the approach of directly sequencing mtDNA from isolated mitochondria derived from fresh frozen brain samples.
Our data show that different types of mitochondrial rearrangements are very common in both the aging brain and Alzheimer's disease (AD) brain. Three types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched controls. These observed rearrangements include deletion, F-type rearrangement, and R-type rearrangement. F-type rearrangement is defined as fragments with two different sections of mtDNA joined together in the same direction. R-type rearrangement is defined as rearrangement of mtDNA originating from two different orientations of mtDNA fragments. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9% versus 6.7%). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%).
Evidence indicates that mitochondrial dysfunction has an early and preponderant role in Alzheimer's disease. Our data supports this, as the AD brain samples had more than 2.7 times the recombinant rate of similarly-aged controls. Significantly, the rate for deletion in AD was 4 times that of the control samples. The position of deletion joining points was not evenly distributed across the entire genome and instead was concentrated between regions 6kb and 15kb of the mitochondrial genome, which happens to be the area containing the DNA sequences for synthesizing all three cytochrome oxidases necessary for correct electron transport chain function. This makes it is reasonable to advance the concept that increased deletions in this area may affect the ability of mtDNA to synthesize cytochrome oxidase. Our results are consistent with reports of decreased cytochrome oxidase activity in AD brain samples.