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Every cell in the body contains a swarm of mitochondria, responsible for packaging the chemical energy store molecule ATP that is used to power cellular processes. Mitochondria are the distant descendants of symbiotic bacteria, and retain a remnant of the original DNA. This mitochondrial DNA is unfortunately less well protected and maintained than DNA in the cell nucleus. It is thought that a sizable fraction of the declines of aging are caused by accumulated damage to mitochondrial DNA, coupled with progressive failure of the quality control mechanisms responsible for recycling dysfunctional mitochondria. Reducing the functional capacity of cells via a reduction in available energy can produce all sorts of detrimental effects, and while much of the relevant research is focused on the energy hungry tissues of brain and muscle, this is a problem in all tissues.
The mitochondrial organelle, a double-membraned organelle with its evolutionary origins in the eubacterial kingdom, is the central factor in the energy metabolism of the eukaryotic cell. It is responsible for the vast majority of the ATP (adenosine triphosphate) produced in the cell (~90% under normal circumstances), which it produces through oxidative phosphorylation (OXPHOS) by way of a multi-subunit complex called the electron transport chain (ETC). The mitochondrion possesses its own small, circular genome (mtDNA) that encodes key RNA and proteins required for OXPHOS.
The mtDNA mutation rate depends on many factors, including the extent of oxidative stress and the fidelity of the mitochondrial DNA polymerase (POLG). The production of reactive oxygen species (ROS) is an inevitable outcome of the oxidative phosphorylation process that occurs within the mitochondrion, and these chemical byproducts are, by their nature, damaging to DNA. Thus, given its proximity to the source of ROS production, mtDNA experiences a high rate of ROS-induced mutation. ROS production is also increased by pre-existing mtDNA damage, excess calories, regional mtDNA genetic variations, and alterations in nuclear DNA expression of stress response genes, creating a vicious cycle where increased ROS production can encourage the occurrence of even more ROS production over time.
There is a well-established correlation between aging and a decline in mitochondrial function, which likely contributes to age-related senescence and geriatric disease. PolgD257A “mutator” mice – which exhibit increased mtDNA mutation rates – show an accelerated aging phenotype, suggesting that the accumulation of mtDNA mutations over time may be a crucial factor driving the aging of mammals. The age-related decline in mitochondrial function is likely caused, in large part, by the gradual accumulation of somatic mtDNA mutations due to ROS damage and DNA replication errors. This accumulation of mtDNA mutations promotes even more ROS production, establishing a vicious cycle and accelerating the aging process. Although a serious mtDNA mutation can be acquired early in life, for most people it will take several decades to acquire one or more disease-causing mutations and have them reach a sufficiently high level of heteroplasmy to cause serious health issues. This gradual accumulation of mutations and increase in heteroplasmy may help explain the time-dependent decline in function that occurs with age.
Somatically-acquired mtDNA mutations can occur anywhere in mtDNA and may even include large deletions or duplications. Loss of mtDNA integrity (by altered mtDNA copy number or increased mutations) has been implicated in cellular dysfunction with aging. Deletion mutations are an insidious risk because the reduced size of mtDNA molecules carrying large deletions (ΔmtDNAs) gives them a replicative advantage over normal mtDNA.
Any mtDNA molecules containing a deleterious mutation in a coding gene, combined with a D-loop mutation that creates a strong proliferative advantage, would have the potential to create severe issues in old age, particularly if they cause the cell to take on neoplastic properties. Furthermore, this ubiquitous and steadily accumulating mutational load in the mtDNA population will likely create general problems for the ETC function and mitochondrial health, thus contributing to age-related senescence. For these reasons, we believe there is great merit in the argument that mitochondrial defects play a significant role in the development of many common diseases of age. We hypothesize that the diversity of mutations in mtDNA could be decisive for the variability of clinical phenotypes, such as age of disease onset.