Mitochondrial Disorders

By Chandan Sekhon - Medicine Student @ Peterhouse, Cambridge

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The mitochondria are organelles located in cells and are the site of the aerobic stages of respiration. This is crucial to generate molecules of ATP; used for a multitude of active cellular processes including muscle contraction and nerve transmission. The DNA of the cell is in the nucleus, however, there is some DNA in the mitochondria as well (mtDNA). Specifically, 37 genes are located in the mitochondria and there are no introns. This DNA is similar in structure to bacterial DNA (for example, it is circular), forming the basis of the endosymbiotic theory (described further on).

Naturally, mtDNA is prone to mutations (like nuclear DNA), meaning mitochondrial disorders can also result when mitochondrial inheritance is dysregulated, or if mtDNA becomes corrupted. Mitochondria divide stochastically and independently from the nuclear cell cycle. This is likely a result of the evolution of mitochondria from prokaryotic microorganisms. This is the endosymbiotic theory. Evidence for this theory includes their relative sizes being similar to bacteria and how they divide by binary fission as bacteria do. Mitochondria are maternally inherited, and therefore mitochondrial disorders are typically inherited maternally since the sperm doesn’t contribute any mitochondria to the embryo. These can include various mutations - often point mutations (substitutions), insertions or deletions.

There are also variations with the expression of mitochondrial disorders, as in some individuals, each cell carries the same abnormal mitochondria (homoplasmy) but sometimes heteroplasmy can occur when individuals have a combination of both normal and mutant mitochondria. The inheritance pattern shown below in the pedigree diagram (figure 1) shows how abnormal mitochondria are not inherited from affected sons and arises only maternally. This means there is a 100% chance of each child inheriting a mitochondrial disorder if the mother has it.

Figure 1: Pedigree diagram showing inheritance pattern for mitochondrial disorder

An example of a mitochondrial disorder is MELAS syndrome, with possible symptoms including muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. One of the key observations of this disease is a build-up of lactic acid in the blood. MELAS may result from mutations in one of several genes, including MT-ND1 and MT-ND5 (located on the mitochondrial genome, mtDNA). Some of the genes related to MELAS provide instructions for making proteins involved in aerobic respiration and can result in abnormalities regarding this, particularly affecting the brain and muscles. Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80% of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and generate ATP. The repercussions of this could be severe, as respiration is key for numerous processes.

There are no specific treatments available for MELAS with drugs used to manage seizures often observed in patients. As well as this, treadmill training could help improve aerobic capacity and reduce lactate levels in blood. Other treatments are also available to help improve the ability of the mitochondria to generate ATP. Genetic counselling is often recommended to affected patients and families as well.

Further reading:

1. Article about MELAS syndrome in more detail, outlining a detailed disease profile and even goes into current research taking place to develop new treatments for it: https://rarediseases.org/rare-diseases/melas-syndrome/

2. Article outlining the basics behind endosymbiotic theory – a very good introduction to it: https://askabiologist.asu.edu/explore/cells-living-in-cells

3. A much more detailed publication going into the history and research behind endosymbiotic theory – quite challenging but definitely interesting: https://royalsocietypublishing.org/doi/10.1098/rstb.2014.0330

4. Website giving a brief outline of mtDNA and describes related conditions in more detail: https://medlineplus.gov/genetics/chromosome/mitochondrial-dna/#conditions