Genetic foundations of mitochondrial diseases
The normal functioning of mitochondria depends on two genomes; mutations in either can lead to the development of diseases:
- Mitochondrial genome. Represented by circular DNA molecules. It contains genes encoding transfer and ribosomal RNAs (tRNA and rRNA), as well as proteins directly involved in the function of the respiratory chain.
- Nuclear genome. Controls the synthesis of the vast majority of proteins that facilitate the process of oxidative phosphorylation.
Types of inheritance
Depending on the localization of the mutation, there are two main types of transmission for mitochondrial diseases:
- Mendelian inheritance. Occurs when mutations happen in nuclear DNA genes.
- Maternal transmission. Characteristic of defects in the mitochondrial genome.
The mechanism of maternal inheritance is due to the fertilization process: the zygote receives all its mitochondria from the cytoplasm of the maternal egg cell. Paternal mitochondria located in the spermatozoon do not enter the zygote and do not participate in the formation of the embryo.
Clinical presentation and examples
The symptoms of mitochondrial diseases are extremely diverse, but most frequently include:
- Delayed physical development;
- Damage to various structures of the nervous system;
- Myopathies and cardiomyopathies;
- Liver failure.
Classic examples include isolated mitochondrial myopathies and cardiomyopathies, as well as the complex Kearns–Sayre syndrome. This syndrome is characterized by a triad of signs: pigmentary retinopathy, ophthalmoplegia (paralysis of the eye muscles), and cardiomyopathy.
Trinucleotide repeat expansion disorders
A distinct group of hereditary disorders is represented by pathologies caused by dynamic mutations. Their essence lies in an increase in the number of trinucleotide copies within the coding or regulatory region of a gene. This type of mutation has been found exclusively in humans.
Pathogenesis is associated with DNA polymerase dysfunction during DNA replication (in mitosis or meiosis). An important feature: the disease only manifests upon reaching a certain manifestation threshold — when the number of repeats exceeds a critical level.
Example: Huntington's chorea
A classic example of a trinucleotide repeat expansion disorder is Huntington's chorea, a severe hereditary neurodegeneration.
- Mutation localization: short arm of chromosome 4.
- Molecular defect: an increase in the number of cytosine-adenine-guanine (CAG / CAG) repeats in the coding region of the gene. This leads to an excess of glutamine amino acid residues in the synthesized huntingtin protein, which is critical for brain function.
- Clinical course: the disease has a late onset (at 40–50 years of age), relentlessly progresses, and leads to the complete loss of cognitive and motor functions within 5–10 years.
Briefly: answers to topical questions
Which specific enzyme complexes are part of the mitochondrial respiratory chain?
The mitochondrial respiratory chain consists of several specific membrane-bound enzyme complexes.
- Complex I — NADH dehydrogenase (contains the flavin mononucleotide coenzyme).
- Complex II — succinate dehydrogenase (contains the flavin adenine dinucleotide coenzyme and is also an enzyme of the tricarboxylic acid cycle).
- Complex III — $QH_2$ dehydrogenase.
- Complex IV — cytochrome c oxidase.
To memorize the triad of Kearns–Sayre syndrome, use the acronym POC: Pigmentary retinopathy, Ophthalmoplegia, Cardiomyopathy.
Class and exam questions
Why are mitochondrial mutations inherited exclusively from the mother?
All embryonic mitochondria originate from the cytoplasm of the egg cell. The spermatozoon does not transfer its mitochondria to the zygote.
Are mitochondrial diseases always inherited via the maternal line?
No. If a mutation affects the genes of oxidative phosphorylation proteins located in the nuclear genome, inheritance will follow classical Mendelian laws.
What is the essence of the manifestation threshold phenomenon in dynamic mutations?
Clinical symptoms of a disease (for example, in Huntington's chorea) do not arise with any number of trinucleotide repeats, but only when their count exceeds a certain critical level.
What else to study on this topic
- Mechanisms of nuclear protein involvement in oxidative phosphorylation
- Structure and functions of circular mitochondrial DNA
- Pathogenesis of nervous system damage in energy metabolism defects
- Mechanisms of DNA polymerase failure in the formation of trinucleotide repeats
- Functions of the normal huntingtin protein in the brain
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