Mitochondrial DNA Editing in Live Mice
Mitochondrial DNA damage is thought to be important in aging, perhaps contributing broadly to general declines in mitochondrial function, perhaps leading to a small population of highly dysfunctional cells that export damaging oxidative molecules into surrounding tissues. The initial use for biotechnologies that can edit mitochondrial DNA is to fix inherited conditions, in which the mutational damage is the same in many mitochondria throughout the body. The challenge in adapting this approach to age-related mitochondrial DNA damage is that this damage is random, different in every cell it takes place in. It is likely, therefore, that approaches other than mitochondrial DNA editing will receive the most attention and funding when it comes to treating mitochondrial aging.
Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria contains a tiny amount of mitochondrial DNA. Faults in our mitochondrial DNA can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions. There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be treated.
Researchers recently used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. The treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by its cells. The tool looks for a unique sequence of base pairs - combinations of the A, C, G and T molecules that make up DNA. It then changes the DNA base - in this case, changing a C to a T. This would, in principle, enable the tool to correct certain 'spelling mistakes' that cause the mitochondria to malfunction.
There are currently no suitable mouse models of mitochondrial DNA diseases, so the researchers used healthy mice to test the mitochondrial base editors. However, it shows that it is possible to edit mitochondrial DNA genes in a live animal. "This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly."
It is pretty amazing that we now have the nascent ability to modify mtDNA and I can see that it has potential for fixing inherited mistakes. But, honest question, even when we get to the point that we can fix the random mtDNA changes caused by aging using this method, wouldn't it be easier to just send a signal to the mitochondria to begin mitophagy?
I have had this same question for a long time regarding the allogenic expression of the mtDNA researched by SRF. They have made amazing progress in this area. But, I naively wonder why we can't just send in a signal that looks for damaged mtDNA and signals for mitophagy? I'm imaging something like a senolytic, but for mitochondria.
I have especially wondered this since learning that mtDNA travel from cell to cell. It seems to me that the cell would be repopulated with healthy mitochondria. Is this harder than allogenic mtDNA expression? Could someone who understands this better explain this to me or point me to an explanation? Thanks!
@Neil: In the case of the mutations involved in MitoSENS, they are deletions of whole genes that interfere with the mitophagy mechanism (mitochondria are not marked for recycling) but still allow mitochondria to reproduce. Since they are never recycled, they quickly outcompete healthy mitochondria and the whole cell is full of the mutated mitochondria. It's like a mitocancer, so to speak.
You can find the details in Aubrey's book.
@Antonio, thank you. I have read End Aging multiple times and love it. What I am confused about is why allogenic expression of mtDNA is easier than just sending in a signal to kill the mitochondria or the whole cell if it can't be saved, the same as for senescent cells. Getting mtDNA into the nucleus in every cell in the body is a very difficult problem. I have no doubt SRF will figure it out in time. But, given that fresh mitochondria can be infused and taken up by the cells, wouldn't it be easier to just kill the mitochondria that are bad or the whole cell and repopulate it?
For example, consider an Oisin-type solution, an mRNA that checks whether the mitochondria has gone rogue and, if so, kill it (or the cell)?