Mitochondrial Replacement Therapy

~ Written By Surabhi Iyer

Mitochondrial replacement therapy (MRT, sometimes called mitochondrial donation)

is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. It was first used in 1996 by the embryologist Jacques Cohen and others at the Institute for Reproductive Medicine and Science for a cytoplasmic transfer in a human assisted reproduction procedure. In 1997, the first baby was born using this procedure. However, due to ethical objections it has still not very widely come into practice.

It is a well-known fact, that mitochondria is the ‘power house of the cell’ and provides

energy for several of the complex metabolic reactions happening in our bodies on a daily

basis. The primary role of mitochondria is aerobic respiration, that is, oxidative

phosphorylation (OXPHOS) and the production of cellular energy in the form of

adenosine triphosphate (ATP). But, the same mitochondria if damaged due to any

external factor can pose a danger to humans and unfortunately many are unknown of

the dangers possessed by a fault in the mitochondria.

Our bodies are complex mechanisms and external factors can often affect our

mechanisms in dangerous ways. Mutation, one amongst the many examples, can be

extremely lethal to a person exposed to it. The patient who harbours pathogenic

mutations that can cause progressive and lethal diseases with no available cure is often

required to make difficult reproductive choices. The parents then have to switch to

other alternatives such as gamete/embryo donation, selecting normal embryos or

conceptus by genetic testing, or adoption. Although, it’s often observed parents prefer

to have their child with their own genetics and as a result their choices become

narrower and restricted to methods involving correcting the “faulty gene” in early

embryos called germ line germ therapy. However, the consequences of these are passed

on to future offspring irrespective of the modifications being positive or negative

rendering this to be a risky procedure.

The speciality of mitochondria is that they have their own DNA, known as the

Mitochondrial DNA (mtDNA). While we all inherit one set of chromosomes from both

our parents, it is not the same case with mtDNA. The offspring always inherit the mtDNA

only from the mother hence if the mother has mitochondrial diseases it is likely to be

passed on to the offspring too. Some nuclear transfer techniques, also referred to as

mitochondrial replacement therapy (MRT), are considered to be a potential germ line

gene therapy for inherited mitochondrial diseases. This therapy is primarily used for two

purposes the first one being, another form of in-vitro fertilisation wherein some, or in

some cases all, of the future baby’s mitochondrial DNA comes from a third party as the

mother may be a carrier of genes causing mitochondrial diseases. This technique is also

used when autologous mitochondria is used to replace mitochondria in damaged tissue

to restore the tissue to a functional state.

Muscle and nerve cells have especially high energy needs and as a result require a large

amount of mitochondria, hence muscular and neurological problems are common

features of mitochondrial diseases. Other frequent complications also involve impaired

vision, cardiac arrhythmia(abnormal heartbeat), diabetes, stunted growth etc. A fatal

syndrome that can also be passed on to offspring from parents having mitochondrial

diseases is Leigh syndrome. Leigh syndrome is a severe neurological disorder that

usually begins to shows its effects and becomes apparent within the first year of life. A

child suffering from this syndrome has progressive loss of mental and movement

abilities (psychomotor regression) and typically results in death within two to three

years, usually due to respiratory failure or in worse cases, even seizures.

The severity of mitochondrial diseases and its ability to be passed on to offspring makes

it integral to be able to find a possible cure to prevent such diseases. Although, the

parents may not evidently suffer from the disease themselves, being a carrier puts their

offspring at risk as the diseases are often untreatable and the symptoms can only be

alleviated however will continue to persist and eventually may lead to death.

Considering this, the MRT was developed to try and ensure that mitochondrial diseases

do not pass to offspring. MRT uses healthy mitochondria coming from a donor’s egg

whose nucleus has been removed and into which the mother’s nucleus is transferred. In

vitro fertilization (either before or after MRT) produces an embryo that contains nuclear

DNA from the father and the mother with healthy mtDNA from the donor.

However, despite the benefits of this procedure, there have been said to be

disadvantages too associated with this technique. For example, using a foreign donor

DNA in the mitochondria of the child could result in changes in personal traits as well as

metabolism in unforeseen ways. In addition to this, epigenetic effects can also prove to

be a hazard as these environmental influences can alter the way genes work, either

switching them on or off, to produce permanent changes. More so, it is argued that the

child may continue to have unidentified health risks as a side effect of the procedure

that may only be identified at later stages of his/her life and the concept of artificially

using donor mtDNA in the child proves to be a form of a ‘designer baby’ for some,

resulting in ethical objections.

Weighing all the pros and cons, it is although noteworthy that this process can indeed

give a new life to an unborn whose mother has a mitochondrial disease as otherwise it

wouldn’t be wrong to say that the unborn would have a very short life ahead. This

method is still in the process of being legalized in some countries while it has already

been legalized in some and as more tests are done and once the ethical issues and

disadvantages of this process are minimized, this technique is likely to be used by many

couples to secure healthy future for their unborn child.

Mitochondrial Replacement Therapy Process