Our cells each contain hundreds of mitochondria, the descendants of symbiotic bacteria that are responsible for generating the chemical energy store molecule adenosine triphosphate (ATP) used to power cellular activity, as well as being deeply integrated with many other important cellular processes. Mitochondria have their own DNA, structured somewhat differently from the DNA of the cell nucleus. It is more vulnerable to damage, being right next door to energetic mitochondrial processes that generate reactive oxygen species, as well as being called upon to replicate a lot more frequently, leading to an increased incidence of replication errors. Further, its repair processes are different and less effective than those of the nucleus. This is all unfortunate, as the random occurrence of deletion mutations that remove access to critical proteins in the machinery that generates ATP is one of the root causes of aging.
Most damaged mitochondria are removed by quality control processes, just like any other structure in the cell. The culled mitochondria are replaced by replication of the survivors. Not all damage is equal, however. Damage that disables the primary method of generating ATP, the process known as oxidative phosphorylation, produces malfunctioning mitochondria that are broken and harmful to the cell, but also either resistant to quality control or capable of replicating more efficiently than their correctly functioning peers. The clones of any one mitochondrion that suffers this sort of damage take over the mitochondrial population of its host cell quite quickly, and the cell becomes dysfunctional as a result. The harm isn't limited to the cell itself, as it begins to export damaging reactive molecules into the surrounding tissues. This is thought to be one of the mechanisms leading to oxidatively damaged lipids entering the bloodstream, spurring development of atherosclerosis wherever they interact with blood vessel walls.
If we had better DNA repair processes active in the mitochondria, could we avoid this fate, or would it only modestly reduce this contribution to aging? That, as ever, depends on the details, and for any given specific approach to enhanced in situ mitochondrial DNA repair it is hard to say without trying it. Modeling and simulation can only go so far at the moment. The SENS Research Foundation approach to mitochondrial DNA damage is arguably based on improved DNA repair: it involves copying the vulnerable mitochondrial genes into the cell nucleus, altered suitably to enable the proteins produced to find their way back to the mitochondria where they are needed. Nuclear DNA is far more resilient than mitochondrial DNA, and this should minimize the problem to the point at which it is insignificant in comparison to other causes of aging. Is it practical at this time to aim for a similar degree of increased efficiency in existing mitochondrial DNA repair processes as a viable alternative? My suspicion is that the answer will turn out to be no, and that these processes have inherent limits, but it can't hurt to check.
The five-year study reveals how the enzyme TDP1 - which is already known to have a role in repairing damaged DNA in the cell's nucleus - is also responsible for repairing damage to mitochondrial DNA (mtDNA). Mitochondria are the powerhouses of cells, they generate the energy required for all cellular activity and have their own DNA - the genetic material which they rely upon to produce important proteins for their function. During the process of energy production and making proteins, a large amount of rogue reactive oxygen species are produced which constantly attack the DNA in the mitochondria. These attacks break their DNA, however the new findings show mitochondria have their very own repair toolkits which are constantly active to maintain their own DNA integrity.
"Each mitochondria repair toolkit has unique components - enzymes - which can cut, hammer and seal the breaks. The presence of these enzymes is important for energy production. Defects in repairing DNA breaks in the mitochondria affect vital organs that rely heavily on energy such as the brain." Although much research has focused on how free radicals damage the DNA in the cell's nucleus, their effect on mitochondrial DNA is less well understood despite this damage to mtDNA being responsible for many different types of disease such as neurological disorders.
The team further identified a mechanism through which mtDNA can be damaged and then fixed, via a protein called TOP1, which is responsible for untangling coils of mtDNA. When the long strands become tangled, TOP1 breaks and quickly repairs the strands to unravel the knots. If free radicals are also attacking the mitochondrial DNA, then TOP1 proteins can become trapped on the mitochondrial DNA strands, making repair even more difficult. Researchers believe the findings could pave the way for the development of new therapies for mitochondrial disease that boost their DNA repair capacity, or for cancer treatments which could use TDP1 inhibitors to prevent mtDNA repair selectively in cancer cells.
Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of defects in the 3′-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria.
We reveal that TDP1 resolves mitochondrial PDBs (mtPDBs), thereby promoting mitochondrial gene transcription. Overexpression of a toxic form of mitochondrial topoisomerase I (TOP1), which generates excessive mtPDBs, results in a TDP1-dependent compensatory up-regulation of mitochondrial gene transcription. In the absence of TDP1, the imbalance in transcription of mitochondrial- and nuclear-encoded electron transport chain (ETC) subunits results in misassembly of ETC complex III. Bioenergetics profiling further reveals that TDP1 promotes oxidative phosphorylation under both basal and high energy demands. Together, our data show that TDP1 resolves mtPDBs, thereby regulating mitochondrial gene transcription and oxygen consumption by oxidative phosphorylation, thus conferring cellular protection against reactive oxygen species-induced damage.