Mitochondrial DNA (mtDNA) damage is an important cause of degenerative aging. Via a complicated chain of events it leads to a small population of malfunctioning cells overtaken by malfunctioning mitochondria that export harmful reactive compounds into surrounding tissue.
There are a number of possible approaches to fix this issue, reversing its contribution to aging and age-related disease. One of them is to deliver undamaged, replacement mitochondrial DNA to all cells in the body, such as via protofection. The issue with this approach is that mitochondria are essentially like bacteria in the way they reproduce. Certain types of damage to their DNA produce mitochondria that evade cellular quality control mechanisms and outcompete their undamaged peers despite the fact that they are dysfunctional. Delivering fresh undamaged mitochondrial DNA into that cell doesn't get rid of the damaged copies, and the damaged copies have already demonstrated an ability to thrive. The suspicion is that the benefits of such a treatment would be temporary at best.
But what if this delivery of new mitochondrial DNA could be paired up with a means to selectively remove the damaged mitochondrial DNA? Given such a technology it might even be possible to skip the delivery entirely and just remove damaged DNA. This would sacrifice a small number of cells, those in a state of dysfunction that lack any remaining undamaged mitochondrial DNA to recreate a population of working mitochondria. Here is an example of such research; like most work on mitochondrial repair it is focused on inherited mitochondrial disease rather than aging, but could produce a technology platform applicable to aging:
Delivery and selection of mtDNA in mitochondria in a heritable manner is yet to be achieved, so alternative approaches to genetic therapy of primary mitochondrial diseases are being sought. One of these approaches is based on pathogenic mtDNA mutations being generally heteroplasmic, with observable pathology only present when the ratio of mutated mtDNA exceeds a certain threshold. The selective elimination of mutated mtDNA allows a cell to repopulate with wild-type mtDNA molecules by a yet uncharacterized mechanism of mtDNA copy number maintenance, alleviating the defective mitochondrial function that underlies mtDNA disease.
We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site-specific elimination of pathogenic human mitochondrial DNA (mtDNA). Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild-type mtDNA restored mitochondrial respiratory function in a [cell model of mtDNA damage]. This study constitutes proof-of-principle that, through heteroplasmy manipulation, delivery of site-specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species.