Like anything else in the body, even the mitochondria can be afflicted with disease, damage, or anything else detrimental to its function. Mitochondrial diseases (MD) are genetic disorders inherited from the biological parents, random mutations (very rare), or environmental situations . The latter two are rare and I won’t go over them here, but the biological inheritance can be broken down into two groups. The first are MDs inherited from chromosomal DNA and the second group are inherited from the mitochondrial DNA (mtDNA). This brings up a very important difference between the two groups. The first group can come from either biological parents while the second group can ONLY come from the biological mother because we only inherit the mtDNA of our biological mothers. The possibility that MD can arise from the interaction between the chromosomal DNA and mtDNA is currently unknown .
There are many different types of mitochondrial diseases and they all span different causes, symptoms, treatments, occurrence, and many other factors . Because of the varied nature of MD, we will instead look at one circumstance of MD and how that is “cured”. For a full overview of MD, check out the paper by Dr. Patrick Chinnery. The circumstance we will be dealing with is MD as a result of genetic defects in the mtDNA. The “cure” is mitochondrial replacement therapy. The cure is not really a cure since it does not fix the genetic defect, but replaces it.
In those cases where the MD originates from defects due to mtDNA, the biological mother may or may not experience any symptoms because of it. In fact, for some of the MDs, the parents can be carriers of the disease and their children may end up with it. The severity of the defect, which is understood through genetic testing, physical assessments, and analyzing family history, varies. If the defect results in disease it can range from mild symptoms to fatal . The defects can come from a variety of different places. It could come from a family history where it is passed down from mitochondria to mitochondria each generation if it is not fatal . It can come from two individuals who individually carry part of the defect so that their child carries the full defect resulting in a diseased state . It can even come from random mutations that happen over our lifetimes that results in a detrimental mutation (very rare).
For mitochondrial replacement therapy (MRT) to be an option the genetic defect has to be on the mtDNA of a female egg. The defect could have come from a variety of situations and could have a variety of effects. If it is a fatal effect, then the defect is most likely isolated to the female’s egg and does not affect the female or do so minimally. In the case where MRT comes into play, the usual situation is that the egg is fertilized by the sperm and the resulting zygote now has defective mtDNA. This mtDNA will form the template for all future mtDNA in the growing embryo, which results in the defective mtDNA being in all of the mitochondria versus the previous state where it was only in the egg. So, the resulting child would most likely develop some sort of MD based on the defect. If it is fatal, then the pregnancy would either terminate or the child would die immediately or soon after birth. To avoid this, we look to MRT as a solution.
MRT is a very straightforward procedure. There are two MRT procedures and the one described here is called the spindle transfer .To start, the egg from the mother is isolated and its nucleus is removed since it contains the DNA that we inherit from our biological mothers. The mitochondria and its mtDNA are not removed because they are defective. Then, the egg from a consenting donor, who has healthy and functioning mitochondria, is isolated and the nucleus is removed while the mitochondria remain in the egg. Then, the nucleus from the mother is inserted into the egg of the donor, which contains the healthy mitochondria. Then, this egg is fertilized with the sperm of the father to get a zygote without mitochondrial issues. Finally, the fertilized egg is reinserted into the mother through normal IVF procedures. This method has removed the defect that was previously contained in the mother’s mitochondria and allows the resulting embryo to not have to deal with that issue. This method also creates an embryo that contains three distinct DNAs: nuclear DNA from the mother and father and mtDNA from the donor. It is commonly referred to as a three-parent baby, though as I mentioned in the article about mitochondria the mtDNA is very small compared to the nuclear DNA and has minimal effect on the child’s development outside of its mitochondria .
None of this is without ethical issues and some clinical issues as well, but I think that it opens the gate towards addressing genetic diseases that were previously only ever dealt with by treating symptoms rather than the causes. With emerging technologies such as this or even CRISPR, we are slowly but surely getting to a point where we can solve genetic diseases. There will be hurdles, just like anything else in science and life, but it is possible.