The fellow of average scientific literacy, passing by this entry, might wonder "do I care whether or not my damaged mitochondrial DNA is being repaired?" A valid question; I would direct your attention to a previous post that explains what mitochondria are and why damage to their DNA appears to be an important root contribution to the degenerations and frailties of aging - and quite likely to your eventual death:
Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration - but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own metabolism as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your of metabolism are themselves damaged by the free radicals they created.
Take a look; a chain of dominos exists in your cellular biochemistry. It starts with the accumulation of damaged mitochondrial DNA and ends with a good 1% of your cells turned into bloated generators of damaging chemicals. These chemicals spread throughout your body, degrading important systems, causing pain, illness and suffering - until eventually something fails explosively enough to kill you.
So it is probably of interest to most of us just how and when mitochondrial DNA might be repaired. As it turns out, there has been some debate in past years as to whether or not the body does perform these repairs, or is capable of doing so, and what sort of repairs are possible - certainly our biochemistry doesn't appear to be repairing mitochondrial DNA to a level that would prevent the very visible suffering of the elderly. Here are a couple of recent papers that perhaps illustrate where scientists are on this topic at the present time:
Cells of the [central nervous system] CNS are constantly exposed to agents which damage DNA. Although much attention has been paid to the effects of this damage on nuclear DNA, the nucleus is not the only organelle containing DNA. Within each cell, there are hundreds to thousands of mitochondria. Within each mitochondrion are multiple copies of the mitochondrial genome. These genomes are extremely vulnerable to insult and mutations in mitochondrial DNA (mtDNA) have been linked to several neurodegenerative diseases, as well as the normal process of aging. The principal mechanism utilized by cells to avoid DNA mutations is DNA repair. Multiple pathways of DNA repair have been elucidated for nuclear DNA. However, it appears that only base excision repair is functioning in mitochondria.
The role of mitochondria in energy production and apoptosis is well known. The role of mitochondria and particularly the role of the mitochondria's own genome, mitochondrial (mt) DNA, in the process of ageing were postulated decades ago. However, this was discussed, debated and more or less disposed of. Recent data from elegant mouse models now confirm that mutations of mtDNA do indeed play a central and pivotal role in the ageing process. Newer reports also indicate a possible role of mtDNA mutations in the carcinogenesis of several organs. But is damaged mtDNA repaired, or is it simply degraded and discarded? This question appears to be answered now. According to recent data, mitochondria possess functional repair mechanisms such as base excision repair, double-strand break repair and mismatch repair, yet nucleotide excision repair has so far not been detected.
"Some repair" it is then. Why my interest in this in a world in which protofection will be a viable technology in a few short years?
Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection and protein expression in mitochondria of live rats, after an injection of genetically engineered mitochondrial DNA complexed with our protofection transfection agent. A significant fraction of cells in the brain is transfected with this single injection even though we so far did not optimize the dose.
This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.
In other words, if we could just up and replace all our damaged mitochondria at once with a single therapy, why worry about the investigation of repair mechanisms? Well, a wide range of approaches is better than a single approach for starters. Secondly, it's often easier to manipulate an existing biochemical process than to generate an entirely new one. Thirdly, as that first paper notes, scientists have some experience and idea on where to start with improving the performance of existing DNA repair mechanisms.
it appears that only base excision repair is functioning in mitochondria. This repair pathway is responsible for the removal of most endogenous damage including alkylation damage, depurination reactions and oxidative damage. Within the rat CNS, there are cell-specific differences mtDNA repair. Astrocytes exhibit efficient repair, whereas, other glial cell types and neuronal cells exhibit a reduced ability to remove lesions from mtDNA. Additionally, a correlation was observed between those cells with reduced mtDNA repair and an increase in the induction of apoptosis. To demonstrate a causative relationship, a strategy of targeting DNA repair proteins to mitochondria to enhance mtDNA repair capacity was employed. Enhancement of mtDNA repair in oligodendrocytes provided protection from reactive oxygen species and cytokine-induced apoptosis.
Could this sort of repair enhancement be effective enough for this component of the aging process to merit funding on a par with full-on replacement strategies like protofection? Could it do more than just gently slow the accumulation of damage? An interesting question; maybe, maybe not - though I'm leaning towards the latter answer.