Biotechnology is improving rapidly: taking sets of individual cells and looking in the state of DNA inside the mitochondria of those cells is a reasonable exercise for a modest research group nowadays. As expected, neurons in old brains have a bunch of deletions:
Mitochondrial dysfunction is a consistent finding in neurodegenerative disorders like Alzheimer's (AD) or Parkinson's disease (PD) but also in normal human brain aging. In addition to respiratory chain defects, damage to mitochondrial DNA (mtDNA) has been repeatedly reported in brains from AD and PD patients. Most studies though failed to detect biologically significant point mutation or deletion levels in brain homogenate.
By employing quantitative single cell techniques, we were recently able to show significantly high levels of mtDNA deletions in dopaminergic substantia nigra (SN) neurons from PD patients and age-matched controls. In the present study we used the same approach to quantify the levels of mtDNA deletions in single cells from three different brain regions (putamen, frontal cortex, SN) of patients with AD (n = 9) as compared to age-matched controls (n = 8). There were no significant differences between patients and controls in either region but in both groups the deletion load was markedly higher in dopaminergic SN neurons than in putamen or frontal cortex (p < 0.01; ANOVA). This data shows that there is a specific susceptibility of dopaminergic SN neurons to accumulate substantial amounts of mtDNA deletions, regardless of the underlying clinical phenotype.
Deletions are much more important than point mutations when it comes to degrading function in mitochondria, and thereby causing a follow-on chain of issues in a cell and surrounding tissue. You might recall recent work showing mice loaded up with point mutations and perfectly fine for it, for example. Deletions, however, have a much greater chance of knocking out one of the few genes necessary for the effective function of mitochondria.
You can look back in the archives to see what happens when mitochondrial DNA is damaged, and the important contribution this makes to degenerative aging. We should all be supporting and encouraging work on the slate of potential technologies to repair, replace, augment, and move mitochondrial DNA:
- The MitoSENS approach - move it to the nucleus
- Replacement via protofection
- Restore function via the (tRNA) mechanisms of Leishmania
- Another tRNA approach
Other potential methods exist in a more speculative state, such as using engineered bacteria to consume damaged mitochondria, or xenotransplantion of new mitochondria from other species. The breadth of potential approaches is growing, which is a good sign, but the field isn't moving fast enough for my liking at this time. More funding and attention is needed.