Mitochondrial diseases

Mitochondrial diseases are a large heterogeneous group of hereditary diseases and pathological conditions caused by structural disorders, mitochondrial functions and tissue respiration. According to foreign researchers, the incidence of these diseases in newborns is 1: 5000.

ICD-10 code

Metabolic disorders, class IV, E70-E90.

A study of the nature of these pathological conditions was initiated in 1962, when a group of researchers described a patient of 30 years with non-thyroid hypermetabolism, muscle weakness and a high level of basal metabolism. It was suggested that these changes are related to a disturbance in the processes of oxidative phosphorylation in the mitochondria of muscle tissue. In 1988, other scientists reported for the first time the detection of a mutation in mitochondrial DNA (mtDNA) in patients with myopathy and optical neuropathy. After 10 years, mutations of nuclear genes encoding respiratory chain complexes in young children were found. Thus, a new direction has been formed in the structure of childhood diseases: mitochondrial pathology, mitochondrial myopathies, mitochondrial encephalomyopathies.

Mitochondria are intracellular organelles present in the form of several hundred copies in all cells (except for erythrocytes) and producing ATP. The mitochondrial length is 1.5 μm, the width is 0.5 μm. Their renewal occurs continuously throughout the cell cycle. Organellum has 2 membranes - external and internal. From the inner membrane inward folds, called cristae. The interior space fills the matrix - the main homogeneous or fine-grained substance of the cell. It contains a circular DNA molecule, specific RNA, granules of calcium and magnesium salts. On the inner membrane, enzymes involved in oxidative phosphorylation (cytochrome b, c, a and a3 complex) and electron transfer are fixed. It is an energy-transforming membrane that converts the chemical energy of oxidation of substrates to energy that accumulates in the form of ATP, creatine phosphate, etc. Enzymes involved in transport and oxidation of fatty acids are concentrated on the outer membrane. Mitochondria are capable of self-reproduction.

The main function of mitochondria is aerobic biological oxidation (tissue respiration using an oxygen cell) - a system for using energy of organic substances with its phased release in a cell. In the process of tissue respiration, the hydrogen ions (protons) and electrons are sequentially transferred 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 hydrogen ions formed are accepted by adenine nucleotides-adenine (NAD ⁺ ) and flavin (FAD ⁺ ) nucleotides. The restored coenzymes NADH and FADH are oxidized in the respiratory chain, which is represented by 5 respiratory complexes.

During the transfer of electrons, energy is stored in the form of ATP, creatine-phosphate and other macroergic compounds.

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

• The first complex is 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, is encoded only by mtDNA);
• 3rd complex - cytochrome C-oxidoreductase (transfers electrons from coenzyme Q to complex 4, consists of 9-10 proteins, synthesis of one of them is encoded by mtDNA);
• The 4th complex - cytochrome oxidase [consists of 2 cytochromes (a and a3), encoded by mtDNA];
• The 5th complex is mitochondrial H ⁺ -ATPase (consists of 12-14 subunits, carries out the synthesis of ATP).

In addition, electrons of 4 fatty acids undergoing beta-oxidation transfer an electron-carrying protein.

Another important process in mitochondria is the beta-oxidation of fatty acids, which results in the formation of acetyl-CoA and carnitine esters. In each cycle of oxidation of fatty acids, 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 the mitochondria have their own unique genome, inherited from the maternal line. It is represented by a single small ring chromosome 16 569 bp long, encoding 2 ribosomal RNAs, 22 transport RNAs and 13 subunits of enzyme complexes of the electron transport chain (seven of them belong to complex 1, one to complex 3, three to complex 4, two - to the complex 5). Most mitochondrial proteins involved in oxidative phosphorylation (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 function of mtDNA is different from the nuclear genome. First, it does not contain introns, which provides a high density of genes 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 were also revealed. Especially it should be noted that there is a large number of copies of the first. Each mitochondria contains from 2 to 10 copies or more. Considering the fact that cells can have hundreds and thousands of mitochondria in their composition, up to 10,000 copies of mtDNA are possible. It is very sensitive to mutations and at present three types of such changes have been identified: point mutations of proteins encoding mtDNA genes ( mutations), point mutations of mtDNA-tRNA genes (sy / 7 mutations) and large mtDNA (p- mutations).

Normally, the entire cellular genotype of the mitochondrial genome is identical (homoplasm), however, when a mutation occurs, a part of the genome remains identical, and the other is changed. This phenomenon is called heteroplasmia. The manifestation of the mutant gene occurs when the number of mutations reaches a certain critical level (threshold), after which there is a violation of the processes of cellular bioenergetics. This explains the fact that with the minimum violations, the most energy-dependent organs and tissues (nervous system, brain, eyes, muscles) will suffer first of all.

Symptoms of mitochondrial diseases

Mitochondrial diseases are characterized by a pronounced variety of clinical manifestations. Since the most volatile systems - the muscular and nervous systems, they are affected first of all, so the most characteristic signs develop.

Symptoms of mitochondrial diseases

Classification

A single classification of mitochondrial diseases does not exist because of the uncertainty of the contribution of nuclear genome mutations to their etiology and pathogenesis. Existing classifications are based on 2 principles: the participation of a mutant protein in oxidative phosphorylation reactions and whether the mutant protein is encoded by mitochondrial or nuclear DNA.

Classification of mitochondrial diseases

[1], [2], [3], [4], [5], [6], [7], [8]

Diagnosis of mitochondrial diseases

Morphological studies in the diagnosis of mitochondrial pathology are of particular importance. Due to the great informative importance, it is often necessary to perform a biopsy of the muscle tissue and histochemical examination of the obtained biopsy specimens. Important information can be obtained by simultaneous examination of the material by light and electron microscopy.

Diagnosis of mitochondrial diseases

[9], [10]

Treatment of mitochondrial diseases

To date, effective treatment of mitochondrial diseases remains an unresolved problem. This is due to several factors: the difficulties of early diagnosis, the poor knowledge of individual links in the pathogenesis of diseases, the rarity of some forms of pathology, the severity of the condition of patients due to the multisystemic nature of the lesion, making it difficult to assess the treatment being conducted, and the lack of a unified view of the effectiveness of therapy. Ways of drug correction are based on the knowledge gained on the pathogenesis of individual forms of mitochondrial diseases.

Treatment of mitochondrial diseases