Fight Aging!

Mitochondria are the power plants of the cell, deeply integrated into many core cellular processes, but most importantly, responsible for generating the energy store molecule adenosine triphosphate (ATP), used to power cellular processes. Mitochondria are descended from ancient symbiotic bacteria, and act like bacteria in many ways, fusing and dividing, and passing around component parts promiscuously. Every cell contains a herd of hundreds of these organelles, monitored by quality control processes that destroy worn mitochondria in order to maintain overall function.

Importantly, mitochondria contain their own small circular genome. Mitochondrial DNA is less well protected than that of the cell nucleus, and more prone to stochastic mutational damage. There are clearly types of mitochondrial DNA damage, large deletion mutations that remove genes essential to the electron transport chain, central to mitochondrial function, that result in pathological damage to cells. But mitochondria throughout the body undergo a declining function with age that seems to have more to do with altered dynamics and the failure of mitophagy to keep up with worn mitochondria, a consequence of age-related changes in gene expression of crucial proteins.

Yet mutational damage other than deletions, such as point mutations, is widespread across mitochondria in aged tissues. To what degree is this stochastic mutational damage important as a contribution to age-related mitochondrial decline? Is it as relevant as loss of mitophagy? Unimportant in comparison? Today's open access paper reviews what is known on this topic. It is a complicated situation, still much debated, with mixed evidence on all sides.

The Complicated Nature of Somatic mtDNA Mutations in Aging

With only a few noted exceptions, mitochondria are the main source of cellular energy in eukaryotes. These organelles process dietary reducing equivalents and oxygen through the electron transport chain (ETC) to produce ATP via oxidative phosphorylation (OXPHOS). Mitochondria are involved in other important cellular functions. To varying extents, different cell types rely on these different functions, which, in turn, determines their intracellular localization, dynamics, number, and respiratory flux. As organisms age, these different mitochondrial processes degrade to differing extents and in tissue specific ways. A lingering question in the field of aging biology concerns the source of this dysfunction.

As a consequence of an endosymbiotic event ∼2 billion years ago that gave rise to mitochondria, these organelles have retained a small rudimentary genome that, in animals, is comprised of a circular double-stranded DNA molecule (mtDNA) present in dozens to thousands of copies per cell. The relatively small genome is extremely compact and encodes a total of 37 genes: 22 tRNAs, two mitochondrial ribosomal RNAs, and 13 peptides that comprise essential components of the ETC. As such, proper maintenance of the genetic information is essential for energy production and therefore maintaining cell homeostasis. One long-standing hypothesis in aging research is that the loss of genetic information encoded by the mtDNA is an important driver of aging.

With limited DNA repair capacity and higher replicative index, mtDNA has a substantially higher de novo mutation rate compared to nuclear DNA. The mitochondrial genome is maternally inherited, with most mtDNA within a cell and organism being an exact copy of the original maternal mtDNA pool, a phenomenon known as homoplasmy. However, mtDNA is susceptible to mutations within the germline, which can result in a number of devastating maternally inherited diseases. In addition to causing overt disease, mtDNA mutations can be present at lower levels, a condition known as heteroplasmy. The heteroplasmic allele fraction can range from very low levels to near homoplasmy and can be inherited or occur de novo within somatic tissues during aging and development.

Because of the multi-copy nature of mtDNA, it is estimated that the phenotypic threshold for pathogenic heteroplasmies is ∼60-90% of mitochondrial genomes within a cell. To add more complexity to the condition of heteroplasmy, the occurrence and frequency of mtDNA mutations may have different outcomes depending on the timing of their occurrence, the specific tissue in which they arise, and the total mtDNA content of the cell. Despite decades of study, the complex nature of mitochondrial genetics has made the exact role of somatic mtDNA mutations in aging difficult to discern.

In this review, we focus on the complicated observational and experimental evidence suggesting that, at least in some capacity, somatic mtDNA mutations are involved in the aging process with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging possibilities that offer potential ways forward to increase our understanding of somatic mtDNA in the aging process.