A3243G In a nutshell, how the A3243G mtDNA mutation causes problems.

In a nutshell, here is how the A3243G mtDNA mutation causes problems.

Inside every cell, (apart from the exceptions which prove the rule), there are various tiny organelles. The important ones for this discussion are the Nucleus and the Mitochondria.

The Nucleus contains lots of DNA, about 3 thousand million base pairs. DNA is made of two strands of DNA – each strand being the opposite of the other. DNA codes how to make proteins. Humans have about 45,000 different proteins. Each protein is made up of just 20 Amino Acids, combined in endless permutations.

There is also a little bit of DNA inside the Mitochondria, and although it is very small, just 16.5 thousand base pairs, it’s role is crucial.

Because this discussion uses both types of DNA, the DNA from the Nucleus is unsurprisingly called Nuclear DNA, or nDNA for short, while the DNA from the Mitochondria is unsurprisingly called Mitochondrial DNA, or mtDNA for short.

Mitochondria convert food, glucose and fats into usable energy in the form of ATP, (this ATP is a ‘universal currency of energy’).

In order to do the final step of converting food into ATP, the Mitochondria use several groups of proteins, called Complex I (one) through to Complex V (five).

The Complexes I to V are made up of about 100 proteins. Complex I is the largest with 45 proteins.

Most of these proteins, (about 83), are coded by nDNA, but crucially, there are 17 proteins coded by mtDNA.

In order to make protein, the process is virtually identical between nDNA and mtDNA. This process is summarized below.

The two twisted strands of DNA splits into two and an opposite copy of the main strand is made by a Messenger RNA, or mRNA for short.

The mRNA travels to a Ribosome.

The Ribosome is an “engine” for producing proteins. The Ribosome uses the mRNA as the template for which protein to make. The Ribosome “walks” along the mRNA and uses the code on the mRNA to decide which Amino Acid to join onto the growing Protein.

The code on the mRNA is in groups of 3, and is called a Codon. Thus an mRNA strand contains many Codons, each Codon specifying an Amino Acid on a protein.

There are two steps involved to deliver the correct Amino Acid to the Ribosome.

1/ A Transfer RNA, called tRNA for short, needs to pick up an Amino Acid. There are 20 Amino Acids, and there are 20 matching tRNAs.

2/ Once a tRNA has got an Amino Acid, it hangs around a Ribosome, until the Ribosome needs the Amino Acid which this particular tRNA is carrying.

After delivering the Amino Acid to the Ribosome, the tRNA goes back to step 1 to pick up another Amino Acid.

The mechanism governing both the picking up of the correct Amino Acid and the mechanism for delivering the correct Amino Acid to the Ribosome is basically the same mechanism as the way DNA is a pair of opposite DNA.

In the above process, there is also a set of opposites – the series of Codons on the mRNA and the opposite code, the Anti-Codon on the tip of each tRNA.

Crucial to the steps 1 and 2 above, is the exact shape of the tRNA. Each of the 20 tRNA has a slightly different shape.

This exact shape is the crux of the problem.

The A3243G mutation is on the part of the mtDNA which codes one of the 20 tRNAs, the one which picks up, and delivers, the Amino Acid Leucine, and is not surprisingly called tRNA(Leu).

The A3243G mutation is just “round the corner” from the tip of the tRNA, the Anti-Codon, and unfortunately changes slightly the shape of the tRNA.

Because of the changed shape, the tRNA is not efficient at picking up the Amino Acid Leucine, (a process called Aminoacylation), or at delivering the Amino Acid Leucine when the Ribosome wants one. Sometimes a different Amino Acid is substituted for Leucine in the growing protein.

The end result is that the 13 proteins that are built by the mtDNA are not built correctly.

Because these proteins are involved in the final step of converting food into the usable form ATP, this energy generating process does not proceed very well and the cell is “starved” of energy.

How this mutation affects a patient varies according to a number of factors.

In each cell there are many Mitochondria and inside each Mitochondrion there are many copies of mtDNA.

While the A3243G mutation occurs on some copies of the mtDNA, other copies are correct. The percentage of mutated mtDNA to correct mtDNA is known as the Heteroplasmy level.

If the Heteroplasmy level is high, the individual probably has worse symptoms earlier in life, than someone with a low Heteroplasmy level. Indeed there are many carriers of the A3243G mtDNA mutation who have no symptoms at all.

Although the Heteroplasmy level is usually measured in a patient at the tissue level, (e.g. blood or muscle), the Heteroplasmy level is really at the individual cell.

The cells with a higher Heteroplasmy level are more inefficient at producing energy, so more and more mitochondria are produced to try to compensate. Eventually the cell can become almost entirely composed of Mitochondria. This is often visible in muscle cells stained to show up Mitochondria. These muscle cells are called “Ragged Red Fibres”.

Because an embryo grows from just one cell which divides into 2, then 4, then 8, etc – eventually differences in Heteroplasmy level in neighbouring cells become the Heteroplasmy level of entire organs. Therefore one patient may be OK in Muscles but be affected in Nerves, or vice versa.

This also explains the fact that as a girl grow to become a woman, each of her eggs may have a different Heteroplasmy level, so when these eggs become fertilised and grow into children, the resulting siblings can have widely varying Heteroplasmy levels.

Different types of tissues have different energy requirements, and therefore have different Threshold levels of Heteroplasmy before that tissue shows problems.

The cells which use most energy are the muscles and nerves, thus it is these tissues which give problems first. In medical jargon this is Encephalomyopathy, encephalo(brain) myo(muscle) pathy(disease):

However, the major problem for many patients is Lactic Acid. Everybody is familiar with the burning sensation that comes with over use of muscles, (such as when running). In this circumstance not enough Oxygen is being delivered by heart and lungs and reaching the inside of the cells for the process of breaking down foods fully. Instead only a partial breakdown occurs, producing Lactic Acid as a by product. Once you stop running, the Lactic Acid is cleared relatively quickly. Unfortunately in patients who have problems with their mitochondria, the production of Lactic Acid is never ending and it can build up to high levels.

Most devastatingly, patients often suffer from Strokes – or rather “Stroke like symptoms”. Usually a stroke is due to part of the brain being deprived of oxygen due to a blocked artery in the brain and the damage is long lasting. In patients with A3243G, the mechanism seems to be due to “failure” of the arteries in the brain, which leads to the same symptoms as a stroke. The problems caused are sometimes not as permanent as typical strokes.

It is these major symptoms which give the disease its acronym – MELAS, “Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke like symptoms".

Interestingly, the cells in the Pancreas which produce Insulin, use the ratio of ATP as part of the process of releasing Insulin, so any defect in the amount of ATP produced by the Mitochondria, also affects the amount of Insulin released. This partly explains the prevalence of Diabetes in people with A3243G mtDNA mutation.

For some reason, the cells in the ear are more susceptible to energy deficiency, leading to one of the other symptoms often found – “Sensory-neural deafness”.

It is these two symptoms, which lead to the other acronym – MIDD, “Maternally Inherited Diabetes with Deafness”.

Some cells are constantly dividing, e.g. skin and blood. As you may expect, cells which are healthy divide faster, so over time the healthy cells are at an advantage and the average Heteroplasmy levels drops in these cell types. This means that the mutation can sometimes be difficult to find in blood samples. However, in non-dividing cells, such as muscles and nerves the levels of Heteroplasmy are stable or may even increase over time.

Everyone knows that half of the nDNA comes from each of the parents, however, the mitochondrial DNA, mtDNA, all comes from the mother. Therefore it is described as showing Maternal Inheritance. This has important consequences for genetic counselling.

A man with the A3243G mtDNA mutation cannot pass it on to his children.

For a woman with the A3243G mtDNA mutation the situation is more complicated. Because of the concept Heteroplasmy there is no exact relationship between the Heteroplasmy level of the mother and the Heteroplasmy level of her children. In any child it may be higher or it may be lower. Even if it is higher, it may be in tissues which have a high Threshold level and the child may not have any symptoms.

See Also
A3243G
Amino Acids
Aminoacylation
Anticodon
ATP
Codon
Complexes I to V (one to five)
DNA
Encephalomyopathy
Heteroplasmy
Lactic Acid
MELAS
MIDD
Mitochondria
mRNA
mtDNA
Ragged Red Fibres
Ribosome
Threshold
tRNA
tRNA(Leu)

Maternal Inheritance of mtDNA

We comply with the HONcode standard for health trust worthy information: Verify here.

Copyright © 2002 - Andy Collinson. All Rights Reserved.

Terms Privacy Funding