The three-parent effect: Discussing mitochondrial diseases and epigenetics

20160826110000, Brenda Lau
Is mitochondrial DNA replacement therapy the best way to eradicate mitochondrial diseases? Can the surrogacy process affect the mitochondrial DNA of the child?
The mitochondria is possibly a hiccup in natural selection and evolution.

They are not native and did not evolve in the primordial eukaryote. Studies have found that mitochondria are probably an invasion of a bacteria into the eukaryotic cell. They have their own limited DNA of 37 genes and have RNA and have somewhat developed as though they have their own life form. Well, they did.

Currently, the mitochondria is believed to be the evolutionary result of the incorporation of a bacterium probably 1.7 to 2 billion years ago – but whether the host cell took it in or the bacteria invaded the host cell or some sort of symbiotic combination occurred, is still unknown.

However it happened, the mitochondria are here to stay and are part of every cell in the human body - except the red blood cells. They are essential to life and as they carry DNA, they are involved in their own form of reproduction, which also means they are subject to mutation.

Therefore, when mitochondrial genes mutate or something wrong occurs within the mitochondrial genome, disease can arise. Rare, but still able to happen to approximately one in 4,000 people. Significantly, mitochondrial disease are mostly fatal.

We get our mitochondrial DNA from our mother. It begins when we were embryos, when the mitochondria in the sperm are marked with a regulatory protein known as ubiquitin, for eventual destruction.

Mitochondrial diseases can occur in a couple of ways, but boils down to the embryo having more than one type of mitochondrial DNA. This is termed as 'heteroplasmy'.

Regardless of whether the mother's own mitochondrial genes are defected or the sperm's mitochondrial DNA is not wiped out due to a mistake by the nature of reproduction or a child receives a percentage of mitochondrial DNA from its surrogate mother, the child would have a risk of suffering from a mitochondrial disease.

Mitochondrial DNA replacement therapy


Genomic analyses have advanced in recent times and now it is possible to identify if the mother's mitochondrial DNA whether mutations occurred to give rise to mitochondrial diseases. This identification helps with the prevention of passing mitochondrial diseases to the next generation.

If a woman's mitochondrial DNA does contain genetic mutations or problems that may lead to mitochondrial diseases, another woman whose mitochondrial DNA is error-free is selected. Oocytes from both women are extracted, following which the nuclei of both oocytes are extracted.

The nucleus of the woman with the genetically problematic mitochondria will be inserted into the nucleus-free oocyte of the other woman, which still contains her error-free mitochondria. Afterwards, a sperm from the father is inserted to fertilise the egg. The embryo will then be inserted into the uterus of the mother or a surrogate mother.

This points towards the fact that the child contains DNA from three different individuals: two women and one man. This obviously raises many ethical questions as to whether the woman who donated her mitochondria should be in the picture or not. Genetically, there is still a question of whether there would be future complications that could lead to medical problems.

It should be emphasised that so far no child has been born from this procedure.

The possible resilience of sperm mitochondrial DNA


Another scenario is presented whereby there is inheritance of paternal mitochondrial DNA. It should not happen as paternal mitochondria have a "suicide mechanism" whereby they breakdown upon contact of the sperm with the oocyte.

However it is possible.

In 2002, researchers detailed a case in which a Danish man was discovered to have a mutation on mitochondrial DNA that was derived from his father, resulting in mitochondrial myopathy, a neuromuscular disease. His muscles absorbed very little energy despite the good condition of his hearts and lungs, therefore he suffered from extreme fatigue during and after exercise.

Scientists suspect that this mutation occurred spontaneously after conception, rather than it being inherited directly from his father.

Unfortunately there is no direct cure for this, but researchers from the University of Missouri have taken a step forward recently. They have succeeded in creating heteroplasmic embryos, with specifically paternal mitochondrial DNA being present in the embryo.

Peter Sutovsky, a professor of reproductive physiology and lead author Won-Hee Song, a doctoral candidatefrom Mizzou College of Agriculture, Food and Natural Resources, have prevented paternal mitochondrial DNA removal in pig embryos.

This leads to better understanding of the automatic process of paternal mitochondrial DNA being removed and also creates a method for scientists to study treatments for mitochondrial diseases in humans as well as the significance of mitochondrial inheritance for livestock.

"As many as 4,000 children are born in the U.S. every year with some form of mitochondrial disease, which can include poor growth, loss of muscle coordination, learning disabilities and heart disease," Sutovsky said. "Some scientists believe some of these diseases may be caused by heteroplasmy, or cells possessing both maternal and paternal mitochondrial DNA. We have succeeded in creating this condition of heteroplasmy within pig embryos, which will allow scientists to further study whether paternal heteroplasmy could cause mitochondrial diseases in humans."

The team identified two separate ubiquitin-binding proteins - SQSTM1 and valosin-containing proteins (VCP) - which they believed were responsible for removing paternal, sperm-contributed mitochondria and their genetic cargo. Upon inhibiting both proteins, the removal process halted.

"This research is important because we now know for sure what processes lead to the deletion of paternal mitochondrial DNA from embryos," Sutovsky said. "This knowledge will enable us to further explore how some children may develop devastating mitochondrial diseases. From there, we can create treatments and therapies that may help prevent or reduce the effects of heteroplasmy and other mitochondrial disorders."

The transfer of DNA between a surrogate and the fetus


Most times, a surrogate mother is needed when a woman is infertile as her uterus is unfit to carry a child. However, studies have shown that surrogate mothers have the ability to affect the DNA of the child she is carrying.

It is due to the placenta, which separates the developing baby from the mother and only allows nutrients and waste to go back and forth. It does not allow blood or other cells from the mother or child to pass through.

In theory, no DNA gets through either. However, sometimes the placenta isn't perfect and DNA between the child and mother can interchange.

It is more common for the DNA of a child to get into the mother; however it can happen vice versa. At one time, this was thought to be very rare. But some recent studies have found a few cells from the mother pass into the child in around 40% of pregnancies.

These cells have the possibility to stick around and this is known as fetomaternal chimerism.

The number of these cells are too tiny to see a significant genetic - including mitochondrial - effect on the child, however a surrogate mother could affect how the DNA is eventually used and this can affect the child for the rest of his or her life.

This three parent effect is possible due to epigenetics - how genetics are shaped by environment.

For example, a fetus with healthy DNA could still be born as a child with birth defects if the surrogate mother smokes or drinks while pregnant. The environment she creates in her womb changes the way the fetus' DNA behaves and could possibly trigger a reaction from the child's mitochondrial DNA - either mutation or over-replication.

So it is fair to claim that a surrogate mother could affect the child's genes as it is affected by the womb where it grows. Although no cases of mitochondrial diseases point towards the transfer of cells between mother or surrogate mother and child, the possibility cannot be ruled out. MIMS

Sources:
http://www.eurekalert.org/pub_releases/2016-08/uom-ndi082216.php
http://genetics.thetech.org/ask/ask420
http://www.nytimes.com/2016/06/24/science/mitochondrial-dna-mothers.html?_r=0
https://www.newscientist.com/article/dn2716-mitochondria-can-be-inherited-from-both-parents/
http://scitechstory.com/2012/11/04/overcoming-mitochondrial-diseases-by-having-three-parents/
http://io9.gizmodo.com/5933490/the-rise-of-the-three-parent-family
http://www.epibeat.com/aging-environment-disease/mitochondrial-epigenetics/2392/


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