There is a constantly replicating herd of mitochondria in every cell, the evolved descendants of ancient symbiotic bacteria now well integrated into cellular mechanisms. They still bear a small remnant of the original bacterial DNA, however, and this is prone to mutational damage. Some forms of this damage cause mitochondria to both malfunction and become more resilient or more able to replicate than their peers. As a result, the cell is quickly overtaken by broken mitochondria and becomes broken itself, exporting damaging reactive molecules into surrounding tissues, the bloodstream, and the body at large.
This process is one of the root causes of aging, so it is a matter of considerable interest to the research community to understand exactly how it is that these damaged mitochondria can so quickly replicate to fill a cell with their descendants. That said, the beauty of the SENS rejuvenation research approach to the problem is that it really doesn't depend on how the damage occurs or spreads. It aims to place backup copies of mitochondrial genes into the cell nucleus, thus ensuring that there is always a supply of the proteins encoded in mitochondrial DNA. So if mitochondrial DNA does become damaged, then there are no further consequences, and mitochondria will nonetheless continue to function correctly.
An intriguing hallmark of aging in mammals is the appearance of cells carrying significant burdens of mitochondrial DNA (mtDNA) mutants. Unlike the mtDNA mutations which cause inherited diseases, those associated with aging appear to be somatically acquired. Within a given tissue, there is often considerable heterogeneity in the burden of mtDNA mutations, such that affected cells co-exist side by side with healthy cells that carry few, if any, mutations. Furthermore, the frequency of affected cells tends to increase with age and there is evidence that within individual cells, the mitochondrial population is commonly overtaken by a single mutant type, very often a deletion in which a part of the normal mtDNA genome has been lost. The precise mutations tend to differ from one affected cell to another, suggesting that individual mtDNA mutations arise at random. How these mtDNA mutations undergo clonal expansion is a question of longstanding interest.
The possibilities that they multiply either because of a so-called vicious cycle such that defective mitochondria simply generate more reactive oxygen species (ROS), which in turn cause more mutations, or because of random drift, have both been considered but found to be unsatisfactory. Instead, it seems most likely that new mtDNA mutations are acted upon by some form of intracellular selection, causing the expansion of a clone of mutant mitochondria that may come to dominate or entirely exclude the wild type population.
Among the various possibilities to account for a selective advantage favoring mtDNA deletions are that: (i) in a cell where wild type and deleted mtDNA molecules co-exist, there may be a selection advantage for deletion mutants since they have a smaller genome size, which might result in a shorter replication time; (ii) if mitochondria that are compromised by a high burden of mutations have a slower rate of metabolism, they may be less damaged by ROS and so relatively spared from deletion by mitophagy, thereby resulting in survival-based selection through a process that has been termed survival of the slowest; (iii) the selection advantage of mtDNA deletions might be based on features relating to some aspect of the machinery for mtDNA replication, of which several possibilities exist, at least hypothetically.
Possibility (i) has been closely examined but found to be implausible, chiefly because the time required for replication of an mtDNA molecule is only a tiny fraction (less than 1%) of the half-life of mtDNA, which drastically diminishes any scope for a size-based replication advantage to be important. Possibility (ii) has also been found to be unlikely, since not only is it incompatible with mitochondrial dynamics, but it also appears that dysfunctional mitochondria are degraded preferentially rather than more slowly than intact ones By a process of elimination, it appears probable, therefore, that the enigma of clonal expansion of mtDNA deletions requires explanation in terms of the machinery for DNA replication.
Recently, we noticed that when the locations of mtDNA deletions, which had been reported from rats, rhesus monkeys, and humans, were compared, there was a stretch of mtDNA that was overlapped in nearly every instance. Based on this observation and noting that the primer required for DNA replication is provided by processing an mRNA transcript, we suggested a novel mechanism based on this intimate connection of transcription and replication in mitochondria. If a product inhibition mechanism exists that downregulates the transcription rate if sufficient components for the respiration chain exist, then deletion events removing a region of the genome involved in this feedback-loop would confer to such deletion mutants a higher rate of replication priming, leading to a substantial selection advantage. In this article, we report additional data from mice that are strongly consistent with our previous analysis of rats, monkeys, and humans, and we further examine the implications of the hypothesis that a shared sequence, falling within the common overlap of these many individual deletions, might throw light on the underlying mechanism for clonal expansion.