Each of our cells contains a herd of mitochondria, the evolved descendants of ancient symbiotic bacteria that now work to generate chemical energy stores used to power the rest of the cell. Mitochondria malfunction in aging, causing their cells to malfunction also, and it is though that this stems from damage to the comparatively fragile mitochondrial DNA. This DNA specifies essential protein machinery used in mitochondrial energy generation, but it sits right next to the ongoing and energetic set of chemical reactions that occur inside each mitochondrion. These reactions generate reactive byproducts - free radicals, reactive oxygen species, and so on - that are most likely to harm the mitochondria rather than any other portion of the cell.
Mitochondria, their state of damage, and their resistance to becoming damaged appear to be very important in determining the pace of aging and longevity of different individuals and species. In particular damage to mitochondrial DNA is important: per the mitochondrial free radical theory of aging, the chain of harm starts with chance mutations that remove just a few essential protein blueprints, but which also allow the damaged mitochondrion to evade cellular quality control mechanisms - so it can reproduce and spread its form of dysfunction.
All of this is why technologies that can replace mitochondrial DNA or move it into the cell nucleus are so important: they will repair and reverse a contributing cause of degenerative aging. Unfortunately it has proven technically challenging to obtain a good picture of what exactly is going in the mitochondrial DNA of laboratory animals, let alone people in clinics. This has probably dampened enthusiasm for the development of means to replace mitochondrial DNA over the past few decades - clinical development proceeds only after great certainty in the underlying science these days, arguably far more certainty than is actually needed to produce good, working therapies. Only comparatively recently has data started to accumulate in earnest, to the point at which it can be seriously applied to support or disprove various different forms of the mitochondrial free radical theory of aging. Here is a whole raft of data to take a look at, however, an example of what researchers are turning out today in terms of mapping mitochondrial DNA damage:
Mitochondrial DNA (mtDNA) rearrangements cause a wide variety of highly debilitating and often fatal disorders and have been implicated in aging and age-associated disease. Here we present a meta-analytical study of mtDNA deletions (n = 730) and partial duplications (n = 37) using information from more than 300 studies published over the last 30 years.
We show that both classes of mtDNA rearrangements are unequally distributed among disorders and their breakpoints have different genomic locations. We also demonstrate that 100% of cases with sporadic mtDNA deletions and 97.3% with duplications have no breakpoints in the 16 071 breakage hotspot site, in contrast with deletions from healthy and aged tissues. Notably, most deletions removing a section of the D-loop are found in tumours. Deleted mtDNA molecules lacking the origin of L-strand replication (OL ) represent only 9.5% of all reported cases, while extra origins of replication occur in all duplications. As previously shown for deletions, imperfect stretches of homology are common in duplication breakpoints.
We provide a dedicated website with detailed information on deleted/duplicated mtDNA regions to facilitate the design of efficient methods for identification and screening of rearranged mitochondrial genomes.
A comprehensive on-line resource with curated datasets of mitochondrial DNA (mtDNA) rearrangements, MitoBreak provides a complete, quality checked and regularly updated list of breakpoints.
Damage to the mitochondrial genome might occur in the form of point mutations, large deletions or duplications and DNA breakage with subsequent linearization of the mtDNA molecule. As eukaryotic cells contain many copies of mtDNA, a mutated type of mtDNA must first reach a threshold level by clonally expanding within a cell before it can cause adverse effects. The accumulation of damaged mtDNA molecules in tissues is an important cause of mitochondrial disease, a clinically heterogeneous group of disorders related with OXPHOS dysfunction. Moreover, mutated mtDNAs are suspected to contribute to the etiology of a number of age-related disorders, by accumulating with age in a variety of tissues.