Mitochondrial diseases

Mitochondrial diseases are a large heterogeneous group of hereditary diseases and pathological conditions caused by disturbances in the structure, functions of mitochondria and tissue respiration. According to foreign researchers, the frequency of these diseases in newborns is 1:5000.

ICD-10 code

Metabolic disorders, class IV, E70-E90.

The study of the nature of these pathological conditions began in 1962, when a group of researchers described a 30-year-old patient with non-thyroid hypermetabolism, muscle weakness and high basal metabolic rate. It was suggested that these changes were associated with impaired oxidative phosphorylation processes in muscle tissue mitochondria. In 1988, other scientists first reported the discovery of a mutation in mitochondrial DNA (mtDNA) in patients with myopathy and optic neuropathy. Ten years later, mutations in nuclear genes encoding respiratory chain complexes were found in young children. Thus, a new direction in the structure of childhood diseases was formed - mitochondrial pathology, mitochondrial myopathies, mitochondrial encephalomyopathies.

Mitochondria are intracellular organelles that are present in the form of several hundred copies in all cells (except erythrocytes) and produce ATP. The length of the mitochondria is 1.5 μm, the width is 0.5 μm. They are renewed continuously throughout the cell cycle. The organelle has 2 membranes - external and internal. From the internal membrane, folds called cristae extend inward. The internal space is filled with a matrix - the main homogeneous or fine-grained substance of the cell. It contains a ring molecule of DNA, specific RNA, granules of calcium and magnesium salts. Enzymes involved in oxidative phosphorylation (a complex of cytochromes b, c, a and a3) and electron transfer are fixed on the internal membrane. This is an energy-converting membrane that converts the chemical energy of substrate oxidation into energy that accumulates in the form of ATP, creatine phosphate, etc. The outer membrane contains enzymes involved in the transport and oxidation of fatty acids. Mitochondria are capable of self-reproduction.

The main function of mitochondria is aerobic biological oxidation (tissue respiration with the use of oxygen by the cell) - a system for using the energy of organic substances with its gradual release in the cell. In the process of tissue respiration, there is a sequential transfer of hydrogen ions (protons) and electrons through various compounds (acceptors and donors) to oxygen.

In the process of catabolism of amino acids, carbohydrates, fats, glycerol, carbon dioxide, water, acetyl coenzyme A, pyruvate, oxaloacetate, ketoglutarate are formed, which then enter the Krebs cycle. The resulting hydrogen ions are accepted by adenine nucleotides - adenine (NAD ⁺ ) and flavin (FAD ⁺ ) nucleotides. The reduced coenzymes NADH and FADH are oxidized in the respiratory chain, which is represented by 5 respiratory complexes.

During the process of electron transfer, energy is accumulated in the form of ATP, creatine phosphate and other macroergic compounds.

The respiratory chain is represented by 5 protein complexes that carry out the entire complex process of biological oxidation (Table 10-1):

• 1st complex - NADH-ubiquinone reductase (this complex consists of 25 polypeptides, the synthesis of 6 of which is encoded by mtDNA);
• 2nd complex - succinate-ubiquinone oxidoreductase (consists of 5-6 polypeptides, including succinate dehydrogenase, encoded only by mtDNA);
• 3rd complex - cytochrome C oxidoreductase (transfers electrons from coenzyme Q to complex 4, consists of 9-10 proteins, the synthesis of one of them is encoded by mtDNA);
• 4th complex - cytochrome oxidase [consists of 2 cytochromes (a and a3), encoded by mtDNA];
• 5th complex - mitochondrial H ⁺ -ATPase (consists of 12-14 subunits, carries out ATP synthesis).

In addition, electrons from 4 fatty acids undergoing beta oxidation are transferred by an electron transport protein.

Another important process takes place in the mitochondria - beta-oxidation of fatty acids, which results in the formation of acetyl-CoA and carnitine esters. In each cycle of fatty acid oxidation, 4 enzymatic reactions occur.

The first stage is provided by acyl-CoA dehydrogenases (short-, medium- and long-chain) and 2 electron carriers.

In 1963, it was established that mitochondria have their own unique genome, inherited through the maternal line. It is represented by a single small ring chromosome 16,569 bp long, encoding 2 ribosomal RNA, 22 transfer RNA and 13 subunits of the enzymatic complexes of the electron transport chain (seven of them belong to complex 1, one to complex 3, three to complex 4, two to complex 5). Most of the mitochondrial proteins involved in oxidative phosphorylation processes (about 70) are encoded by nuclear DNA and only 2% (13 polypeptides) are synthesized in the mitochondrial matrix under the control of structural genes.

The structure and functioning of mtDNA differs from the nuclear genome. Firstly, it does not contain introns, which provides a high gene density compared to nuclear DNA. Secondly, most mRNA does not contain 5'-3' untranslated sequences. Thirdly, mtDNA has a D-loop, which is its regulatory region. Replication is a two-step process. Differences in the genetic code of mtDNA from nuclear DNA have also been identified. It should be especially noted that there is a large number of copies of the former. Each mitochondrion contains from 2 to 10 copies or more. Considering the fact that cells can contain hundreds and thousands of mitochondria, the existence of up to 10 thousand copies of mtDNA is possible. It is very sensitive to mutations and currently 3 types of such changes have been identified: point mutations of proteins encoding mtDNA genes (mit mutations), point mutations of mtDNA-tRNA genes (sy/7 mutations) and large rearrangements of mtDNA (p mutations).

Normally, the entire cellular genotype of the mitochondrial genome is identical (homoplasmy), but when mutations occur, part of the genome remains identical, while the other part is altered. This phenomenon is called heteroplasmy. The manifestation of a mutant gene occurs when the number of mutations reaches a certain critical level (threshold), after which a violation of cellular bioenergetic processes occurs. This explains that with minimal violations, the most energy-dependent organs and tissues (nervous system, brain, eyes, muscles) will suffer first.

Symptoms of mitochondrial diseases

Mitochondrial diseases are characterized by a pronounced diversity of clinical manifestations. Since the most energy-dependent systems are the muscular and nervous systems, they are affected first, therefore the most characteristic signs develop.

Symptoms of mitochondrial diseases

Classification

There is no unified classification of mitochondrial diseases due to the uncertainty of the contribution of nuclear genome mutations to their etiology and pathogenesis. Existing classifications are based on two principles: the participation of the mutant protein in oxidative phosphorylation reactions and whether the mutant protein is encoded by mitochondrial or nuclear DNA.

Classification of mitochondrial diseases

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Diagnosis of mitochondrial diseases

Morphological studies are of particular importance in the diagnosis of mitochondrial pathology. Due to their great informative value, muscle tissue biopsy and histochemical examination of the obtained biopsies are often required. Important information can be obtained by simultaneously examining the material using light and electron microscopy.

Diagnosis of mitochondrial diseases

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Treatment of mitochondrial diseases

To date, effective treatment of mitochondrial diseases remains an unsolved problem. This is due to several factors: difficulties in early diagnosis, poor study of individual links in the pathogenesis of diseases, the rarity of some forms of pathology, the severity of the patient's condition due to the multisystemic nature of the lesion, which complicates the assessment of the treatment, and the lack of a unified view on the criteria for the effectiveness of therapy. The methods of drug correction are based on the achieved knowledge of the pathogenesis of individual forms of mitochondrial diseases.

Treatment of mitochondrial diseases