Reviewing Present Thought on the Cause of Mitochondrial DNA Mutations in Aging
Mitochondria, the power plants of the cell, are the descendants of ancient symbiotic bacteria, and carry a remnant of the original bacterial DNA. This mitochondrial DNA is less well protected and repaired than the DNA found in the cell nucleus, but still encodes a number of vital proteins. Damage to mitochondrial DNA can in some cases produce pathological mitochondria that cause cells to export large numbers of harmful oxidative molecules. This can contribute to the onset and progression of age-related diseases in a number of ways. More generally, mitochondrial DNA damage may produce loss of mitochondrial function with age, but whether or not that is important in comparison to other factors, such as reduced mitophagy, a quality control mechanism that removes damaged mitochondria, is open to question. Why does mitochondrial DNA damage occur? As noted here, opinions on this topic have shifted in recent years.
A major assumption of the free radical theory of aging is that random de novo or somatic mitochondrial DNA (mtDNA) mutations gradually accumulate over time, eventually reaching pathological levels. However, data supports the hypothesis that, rather than gradually accumulating over time, mtDNA turnover can lead to the clonal expansion of pre-existing age-related mutations. Once amplified, these higher frequency mtDNA mutations, that are potentially pathogenic, are referred to as heteroplasmy.
To further understand the potential link between mtDNA mutations and the free radical theory of aging, our group examined aging in the context of tobacco smoking and human immunodeficiency virus (HIV) infection, both believed to accelerate aging. Data suggests that smoking and HIV may distinctly contribute to the accumulation of mtDNA mutations. Indeed, smoking showed an association with increased mtDNA heteroplasmy but not somatic mutations, while the reverse was observed with HIV participants, but only in those with a history of high viremia, reflecting poor control of HIV. These results suggest that the chronic immune activation and subsequent oxidative stress induced by HIV may lead to de novo mtDNA mutations, while oxidative damage associated with exposure to tobacco smoking may promote the clonal amplification of pre-existing mtDNA mutations.
Such a pattern is not consistent with the gradual build-up of random mtDNA mutations. Taken together, our findings do not support the slow accumulation of mtDNA transversion mutations as proposed by the free radical theory of aging. Rather, they suggest that randomly mutated molecules of mtDNA are being clonally amplified to generate unique patterns of heteroplasmy in our participants.
Although the accumulation of mtDNA mutations has been linked to older age and age-associated conditions, several studies have provided new insight that challenge the connection between oxidative damage and mtDNA mutations. For example, the most studied oxidative lesion, 8-oxodG, is one of the 37 major oxidative lesions, and is known to induce transversion mutations (A ↔ C, A ↔ T, C ↔ G, G ↔ T). However, recent studies showing the accumulation of mtDNA mutations with aging did not observe increases in mtDNA transversion mutations, but rather increases in mtDNA transition mutations (A ↔ G, C ↔ T), believed to be the hallmark of mitochondrial polymerase γ errors rather than oxidative damage. Additionally, in our study, although both somatic transition and transversion mutations increased with older age, transition mutations were over 30 times more abundant than transversion mutations, once again suggesting that mtDNA replication errors are the major contributors to mtDNA mutation burden.
In conclusion, recent research support the theory that mtDNA replication errors are the major drivers of cellular mtDNA mutation burden. Nonetheless they do not exclude a comparatively minor role for 8-oxodG-induced transversion mutations, or the many other DNA oxidative lesions that can induce transition mutations. Based on recent findings, an updated understanding regarding the role of free radicals in contemporary theories of mtDNA aging is needed. It seems likely that rather than directly contributing to mtDNA mutations via oxidative lesions, free radicals may affect the mitochondrial polymerase and decrease its fidelity, indirectly increasing somatic transition mutations. Free radicals may also act as a signaling molecule and influence mitochondrial biogenesis and/or mitochondrial turnover via mitophagy, which could in turn promote the clonal expansion of pre-existing mtDNA mutations.