This open access review paper looks over current thinking on the role of mutations in mitochondrial DNA in the decline of stem cell activity in aging. Every cell contains a swarm of mitochondria, the evolved descendants of symbiotic bacteria now responsible for generating chemical energy store molecules. Each contains a small amount of mitochondrial DNA, the last remnant of the original bacterial genome that hasn't either been lost over time or moved to the cell nucleus. Mutational damage in this DNA can produce significant cellular dysfunction, and unfortunately it is a good deal less robust and protected than the DNA of the cell nucleus. It is also right next to energetic chemical processes that produce reactive molecules as a byproduct, and it replicates more frequently than nuclear DNA, all of which suggests a greater rate of damage and error. In long-lived and important stem cell populations, this process is probably important.

Ageing is a process where tissue gradually loses homeostasis and regeneration. This process is systemic and closely associated to age-related changes in somatic stem cells. These cells renew themselves and differentiate into tissue-specific daughter cells for tissue maintenance and regeneration. The age-related alterations in somatic stem cell properties include failure to generate functional progenies, depletion of the stem cell pool, and cancerous transformation. These changes largely affect mitotic tissue, such as blood, intestine, and skin, where the stem cells actively produce progenies to maintain the high turnover of the tissue. However, they also contribute to ageing post-mitotic tissue, such as brain and muscle, though stem cells in these tissues are considered quiescent under normal physiological conditions and activated in response to damage for repairing the tissue.

Mitochondria synthesize ATP via oxidative phosphorylation (OXPHOS) through five multi-subunit complexes. Mitochondria contain their own DNA (mtDNA), which encodes key subunits of these complexes. Replication of the mitochondrial genome is independent of the cell cycle. In addition, mtDNA is susceptible to damage due to lack of histone protection and proximity to oxidative stress. Due to these reasons, compared with the nuclear DNA, mtDNA is more prone to mutations. Multiple copies of mtDNA reside in a cell. Mutations of mtDNA usually occur as a proportion of the total copies and once they reach a threshold, mitochondria will display respiratory chain deficiency, a consequence of which is potentially excessive production of reactive oxygen species (ROS).

Ageing is accompanied by a reduction of mitochondrial function, resulting in respiratory chain defects which are thought to be associated with the accumulation of somatic mtDNA mutations. The age-related change in mitochondria may in turn accelerate the ageing process. Although the significance of mtDNA mutations in various parenchymal cells in normal ageing and age-related degenerative diseases has been broadly studied, the findings might not be able to be extrapolated to stem cells, as they are distinct from somatic cells in terms of biological and metabolic characteristics.

Somatic mtDNA mutations accumulating in stem cell populations in normal humans have a tissue-specific ability to expand clonally during ageing. The premature ageing mtDNA-mutator mouse model gives insight into how acquired mtDNA mutations affect the function of the stem cells and progenitors in both the mitotic and post-mitotic tissue, as well as the potential mechanisms by which age-related mtDNA mutagenesis affects stem cell homeostasis. Recently, studies have reported that stem cells might actively regulate their identity by manipulating the quality control of the mitochondria, for example, by removing the dysfunctional mitochondria or by unevenly segregating young and aged mitochondria. The quality control system might lose its function during ageing, leading to the absence of selective pressures on the somatic mtDNA mutations, which in turn accelerates ageing.