Amutha Boominathan leads the mitochondrial research program at the SENS Research Foundation, focused on achieving allotopic expression of mitochondrial genes. This is the process of placing mitochondrial genes into the nuclear genome, suitably altered so that the proteins produced are transported back to mitochondria where they are needed. Every cell contains a herd of hundreds of mitochondria, the descendants of ancient symbiotic bacteria that contain a remnant circular genome. Mitochondria are responsible for packaging chemical energy store molecules, but are also deeply integrated into many other cellular processes.
Thirteen mitochondrial genes remain in the mitochondrial DNA, the source of proteins vital to the correct operation of these organelles, but far more vulnerable to damage and mutation than nuclear DNA. That damage and mutation is one of the root causes of aging, leading to dysfunctional cells that pump harmful oxidative molecules into the surrounding tissue. Adding backup genes to the cell nucleus should work around this issue by allowing mitochondria with damaged DNA to continue functioning, as they will still receive the necessary proteins.
Your research group started developing an improved method for allotopic expression of mitochondrial DNA in 2015 that has already shown very promising results?
The major hurdle that we have overcome is, at least, showing protein products for all the 13 genes. We made some fundamental changes to all 13 genes with a uniform approach, but that approach may not work equally well for all of them. We may have to engineer each one of them for specific properties. So, all of these 13 genes differ with respect to their length, their hydrophobicity, and the complexes that they target. The main hurdle is actually the hydrophobicity factor. These 13 proteins are normally synthesized within the mitochondrial matrix, and they are inserted into their complexes. But, in allotopic expression, they are synthesized in the cytosol and have to traverse two membranes and then go to the right location. We will have to engineer them one after the other or modify them in such a way that it recognizes the right pathway. So, like I said, we are causing global changes to all 13 genes, and we will cause specific changes to each one of them to make it functional as a whole. The first step is to at least see a product, and that's what we've overcome now.
What have been the criteria for selecting mitochondrial DNA genes to work on for allotopic expression?
One of the other hurdles is proving that your technology actually works, and for that, you need model systems. The reason we were able to show that ATP8 really works is because we were able to get a patient cell line with a severe mutation that's null for the ATP8 protein. Usually, in humans, mutations to mitochondrial genes manifest in various levels, but it is unusual that the protein is completely absent in the patient. It's a rare event. But mitochondrial DNA exists in heteroplasmy. There are wild type and mutant levels, both present continuously, and it's the tipping factor that causes a disease phenotype to ensue. The one reason we were able to really convincingly show ATP8 works is because we were able to get the null cell line and show that the exogenous protein goes into the right location and regains many of the functions that were absent before. Basically, you have the cell line available, which is really rare. So, let's make use of it.
What do you think will be a realistic timeframe for therapies targeting mitochondrial DNA mutations to reach humans?
They are actually already doing that but with the recoded version. That means we already have a precedent. All we have to show is that our version of it is better and that ours has a better immune profile. That's also why we want to do it in animal models, so we can actually show how it's better. I don't know about the timeframe; that's a very difficult question. If the animal studies go well, I want to say five years. Not five years before it reaches people, but five years to establish enough proof of principle that we can start to develop this for people.
In your view, what does aging research need most right now to ensure it can make the most significant leaps that the field is capable of in the coming 10 years?
I think you need good biomarkers. That's lacking in the field. Everybody wants to have a quick fix. They have all these different areas that they think are very important to aging, but I don't think that's the way it is. I think it's more like a general breakdown of everything with time. So you need better markers, and maybe even a better mindset where it's okay to be healthy in old age. People shouldn't be resigned to the fact that they will age with time and that they are going to die. Maybe a little more public education is needed to accept that it's okay to want and to have a healthy lifespan.