Causes of mitochondrial diseases. Mitochondrial pathology and problems of the pathogenesis of mental disorders. What can you do

post updated 02/28/2019

Introduction(features of human mitochondria). A feature of the functioning of mitochondria is the presence of their own mitochondrial genome - circular mitochondrial DNA (mtDNA) containing 37 genes whose products are involved in the process of energy production in the respiratory chain of mitochondria. mtDNA is located in the inner membrane of mitochondria and consists of five conjugated enzyme complexes, which have a total of 86 subunits. They are mainly encoded by nuclear genes (nDNA), but seven subunits of the first enzyme complex (ND1, 2, 3, 4, 4L, 5, 6), one of the third (cytochrome b), three of the fourth (COI, COII, COIII) and two of the fifth (ATPase 6 and 8) are encoded by mtDNA structural genes. Thus, enzyme complexes (i.e., proteins) encoded by both nuclear (nDNA) and mitochondrial genes (mtDNA) are involved in providing diverse biochemical functions of mitochondria.

note! The main biochemical processes that are related to energy metabolism and occur in mitochondria are: tricarboxylic acid cycle (Krebs cycle), beta-oxidation of fatty acids, carnitine cycle, electron transport in the respiratory chain and oxidative phosphorylation. Any of these processes can be disturbed and cause mitochondrial insufficiency.

Cause of mitochondrial disease (hereinafter MB). The main properties of the mitochondrial genome are the cytoplasmic inheritance of genes, the absence of recombinations (i.e., the reorganization of genetic material through the exchange of individual segments, regions, DNA double helixes) and a high mutation rate. The mitochondrial genome is characterized by pronounced instability and a high rate of nucleotide substitutions, on average 10–17 times higher than the mutation rate of nuclear genes, and somatic mutations often occur in it during the life of an individual. The immediate cause of the onset and development of mitochondrial dysfunction lies in defects in the oxidative phosphorylation system, imperfection of repair mechanisms, the absence of histones, and the presence of free oxygen radicals, which are by-products of aerobic respiration.

Mutations in the mitochondrial genome are characterized by the phenomenon [ !!! ] heteroplasmy, in which (due to the specificity of mitochondrial inheritance), as a result of cell division, the distribution (which varies widely - from 1 to 99%) of mutant mtDNA between daughter cells occurs randomly and unevenly, as a result of which copies of mtDNA carrying normal and/or mutant allele. At the same time, different tissues of the body or neighboring areas of the same tissue may differ in the degree of heteroplasmy, i.e. according to the degree of presence and ratio in the cells of the body of mitochondria with both mutant and normal mtDNA (in subsequent generations, some cells may have only normal mtDNA, another part only mutant, and a third part - both types of mtDNA). The content of mitochondria with mutant mtDNA increases gradually. Due to this "lag period" (from the English "lag" - delay), future patients often reach sexual maturity (and give offspring, almost always carrying the same mutations in mtDNA). When the number of mutant copies of mtDNA in a cell reaches a certain concentration threshold, the energy metabolism in cells is significantly impaired and manifests itself in the form of a disease (note: a feature of hereditary MB is often the complete absence of any pathological signs at the beginning of the patient's life).

note! Heteroplasmy is characterized by the simultaneous existence of mutant and normal mtDNA in the same cell, tissue, or organ, which determines the severity, nature, and age of MB manifestation. The number of altered mtDNA can also increase with age under the influence of various factors and gradually reach a level that can cause clinical manifestations of the disease.

In accordance with the above features of the double mitochondrial genome, the type of MB inheritance can be different. Since mtDNA in the body is almost exclusively of maternal origin, when a mitochondrial mutation is transmitted to offspring, a maternal type of inheritance takes place in the pedigree - all children of a sick mother get sick. If a mutation occurs in a nuclear gene (nDNA) encoding the synthesis of a mitochondrial protein, the disease is transmitted according to classical Mendelian laws. Sometimes a mtDNA mutation (usually a deletion) occurs de novo at an early stage of ontogeny, and then the disease manifests itself as a sporadic case.

note! Currently, more than 100 point mutations and several hundred mtDNA structural rearrangements are known to be associated with characteristic neuromuscular and other mitochondrial syndromes, ranging from lethal in the neonatal period of life to diseases with a late onset.

Definition. MB can be characterized as diseases caused by genetic and structural-biochemical defects of mitochondria and accompanied by a violation of tissue respiration and, as a result, a systemic defect in energy metabolism, as a result of which the most energy-dependent tissues and target organs are affected in various combinations: the brain, skeletal muscles and myocardium. (mitochondrial encephalomyopathies), pancreas, organ of vision, kidneys, liver. Clinically, violations in these organs can be realized at any age. At the same time, the heterogeneity of symptoms complicates the clinical diagnosis of these diseases. The need to exclude MB arises in the presence of multisystem manifestations that do not fit into the usual pathological process. The frequency of respiratory chain dysfunction is estimated from 1 per 5-10 thousand to 4-5 per 100 thousand newborns.

Semiotics. Neuromuscular pathology in MB is usually represented by dementia, seizures, ataxia, optic neuropathy, retinopathy, sensorineural deafness, peripheral neuropathy, and myopathy. However, about 1/3 of MB patients have normal intelligence and no neuromuscular manifestations. MB includes, in particular, Kearns-Sayre encephalocardiomyopathy (retinitis pigmentosa, external ophthalmoplegia, complete heart block); MERRF syndrome (myoclonus epilepsy, "torn" red fibers); (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes); Pearson syndrome (encephalomyopathy, ataxia, dementia, progressive external ophthalmoplegia); NAPR syndrome (neuropathy, ataxia, retinitis pigmentosa); and some forms of ophthalmopathic myopathy. All these forms are united by a myopathic syndrome expressed to one degree or another.

note! The two main clinical signs of MB are the increase over time in the number of organs and tissues involved in the pathological process, as well as the almost inevitable damage to the central nervous system. The polymorphism of clinical manifestations, including organ damage, which at first glance are physiologically and morphologically unrelated, combined with different periods of manifestation and the steady progression of disease symptoms with age, makes it possible to suspect an mtDNA [genetic] mutation.

note! In clinical practice, the ability to differentiate the clinical picture of MB from more common somatic, autoimmune, endocrine and other pathological conditions, most of which are treatable, is of great importance. It is necessary to conduct a thorough assessment of the family history, data from routine clinical and laboratory-instrumental methods of examination, before assigning specific genetic and biochemical tests to the patient, aimed at finding mitochondrial pathology.

Diagnostics . The algorithm for diagnosing any MB should include the following steps: [ 1 ] identification of a typical clinical picture of the mitochondrial syndrome or an "inexplicable" multisystemic lesion and a hereditary history confirming the maternal type of inheritance; [ 2 ] further diagnostic search should be aimed at detecting common markers of mitochondrial dysfunction: an increase in the level of lactate/pyruvate in the blood serum and cerebrospinal fluid, a violation of carbohydrate, protein, amino acid metabolism, as well as a clinical picture involving at least three of these systems in the pathological process: CNS, cardiovascular system, muscular, endocrine, renal, organs of vision and hearing; [ 3 ] in case of clinical and confirmed laboratory and instrumental signs of mitochondrial pathology, a PCR analysis of blood lymphocytes is performed for a targeted search for mtDNA point mutations; a study that is considered the gold standard for diagnosing MB [cytopathies] - a biopsy of skeletal muscles with histochemical, electron microscopic, immunological and molecular genetic analyzes, characteristic changes in which will be with any MB (see below); [ 5 ] the most sensitive tests for diagnosing MB are methods for assessing the level of pathological mtDNA heteroplasmy in various organs and tissues: fluorescent PCR, cloning, denaturing high-performance liquid chromatography, sequencing, southern blot hybridization, etc.

Histochemical study of muscle biopsy specimens of patients, including trichrome staining according to the Gomory method, demonstrates changes characteristic of MB - torn red fibers of myofibrils, which contain a large number of proliferating and damaged mitochondria, forming agglomerates along the periphery of the muscle fiber. In this case, the number of torn red fibers in the biopsy should be ≥ 2%. Enzyme-histochemical analysis shows a deficiency of cytochrome C-oxidase in 2 and 5% of myofibrils (for patients younger than 50 and older than 50 years) of their total number in biopsy specimens. Histochemical analysis of succinate dehydrogenase (SDH) activity demonstrates CDH-positive staining of myofibrils (ragged blue fibers), which, in combination with SDH-positive staining of arterial walls that supply blood to muscles, indicates a high degree of damage to myocyte mitochondria. When conducting electron microscopy of muscle biopsy specimens, pathological inclusions, structural rearrangements of mitochondria, changes in their shape, size and number are determined.

note! Despite significant progress since the discovery of mtDNA genetic mutations, most of the diagnostic methods used in clinical practice have a low degree of specificity for individual MBs. Therefore, the diagnostic criteria for a particular MB, first of all, consist of a combination of specific clinical and morphological patterns.

Principles of treatment . Therapy for MB (cytopathies) is exclusively symptomatic and is aimed at reducing the rate of progression of the disease, as well as improving the quality of life of patients. For this purpose, patients are prescribed a standard combination of drugs, including coenzyme Q10, idebenone - a synthetic analogue of CoQ10, creatine, folic acid, vitamins B2, B6, B12 and other drugs that improve redox reactions in cells (electron carrier drugs in the respiratory chain and cofactors of enzymatic reactions of energy metabolism). These compounds stimulate the synthesis of ATP molecules and reduce the activity of free radical processes in mitochondria. Meanwhile, according to a systematic review, most of the drugs with antioxidant and metabolic effects used in MB have not been evaluated in large randomized placebo-controlled trials. Therefore, it is difficult to assess the severity of their therapeutic effect and the presence of significant side effects.

Read more about MB in the following sources:

article "Neuromuscular pathology in mitochondrial diseases" L.A. Saykova, V.G. Pustozers; St. Petersburg Medical Academy of Postgraduate Education of Roszdrav (magazine "Bulletin of the St. Petersburg Medical Academy of Postgraduate Education" 2009) [read];

article "Chronic diseases of non-inflammatory genesis and mutations of the human mitochondrial genome" K.Yu. Mitrofanov, A.V. Zhelankin, M.A. Sazonova, I.A. Sobenin, A.Yu. Postnov; Skolkovo Innovation Center. Research Institute of Atherosclerosis, Moscow; GBOU Research Institute of General Pathology and Pathophysiology of the Russian Academy of Medical Sciences, Moscow; Institute of Clinical Cardiology. A.L. Myasnikova FGBU RKNPK of the Ministry of Health and Social Development of the Russian Federation (magazine "Cardiology Bulletin" No. 1, 2012) [read];

article "Mitochondrial DNA and human hereditary pathology" N.S. Prokhorova, L.A. Demidenko; Department of Medical Biology, State Institution "Crimean State Medical University named after I.I. S.I. Georgievsky", Simferopol (magazine "Tauride Medical and Biological Bulletin" No. 4, 2010) [read];

article "Mitochondrial genome and human mitochondrial diseases" I.O. Mazunin, N.V. Volodko, E.B. Starikovskaya, R.I. Sukernik; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk (journal "Molecular Biology" No. 5, 2010) [read];

article "Prospects for Mitochondrial Medicine" by D.B. Zorov, N.K. Isaev, E.Yu. Plotnikov, D.N. Silachev, L.D. Zorova, I.B. Pevzner, M.A. Morosanova, S.S. Yankauskas, S.D. Zorov, V.A. Babenko; Moscow State University M.V. Lomonosov, Institute of Physical and Chemical Biology named after A.I. A.N. Belozersky, Research Institute of Mitoengineering, Laser Research Center, Faculty of Bioengineering and Bioinformatics; Russian National Research Medical University. N.I. Pirogov (magazine "Biochemistry" No. 9, 2013) [read];

article "Strokes in mitochondrial diseases" N.V. Pizov; Department of Nervous Diseases with courses in neurosurgery and medical genetics, SBEI HPE "Yaroslavl State Medical Academy" (journal "Neurology, Neuropsychiatry, Psychosomatics" No. 2, 2012) [read];

article "Diagnosis and prevention of nuclear-encoded mitochondrial diseases in children" E.A. Nikolaev; Research Clinical Institute of Pediatrics, Moscow (journal "Russian Bulletin of Perinatology and Pediatrics" No. 2, 2014) [read];

article "Epilepsy in children with mitochondrial diseases: features of diagnosis and treatment" Zavadenko N.N., Kholin A.A.; GBOU VPO Russian National Research Medical University. N.I. Pirogov of the Ministry of Health and Social Development of Russia, Moscow (journal "Epilepsy and paroxysmal conditions" No. 2, 2012) [read];

article "Mitochondrial pathology and problems of the pathogenesis of mental disorders" by V.S. Sukhorukov; Moscow Research Institute of Pediatrics and Pediatric Surgery of Rosmedtekhnologii (Journal of Neurology and Psychiatry, No. 6, 2008) [read];

article "Algorithm for the diagnosis of mitochondrial encephalomyopathies" S.N. Illarioshkin (Nervous Diseases magazine No. 3, 2007) [read];

article "Actual issues of treatment of mitochondrial disorders" by V.S. Sukhorukov; Federal State Budgetary Institution "Moscow Research Institute of Pediatrics and Pediatric Surgery" of the Ministry of Health of Russia (journal "Effective Pharmacotherapy. Pediatrics" No. 4, 2012 [read];

article "Leukoencephalopathy with a predominant lesion of the brainstem, spinal cord and increased lactate in MR spectroscopy (clinical observation)" V.I. Guzeva, E. A. Efet, O. M. Nikolaeva; St. Petersburg Pediatric Medical University, St. Petersburg, Russia (journal "Neurosurgery and neurology of childhood" No. 1, 2013) [read];

teaching aid for third-year students of the medical diagnostic faculty of medical universities "Hereditary mitochondrial diseases" T.S. Ugolnik, I. V. Manaenkova; Educational Institution "Gomel State Medical University", Department of Pathological Physiology, 2012 [read];

fast: Mitochondrial diseases(neurodegeneration) - to the site with 17 links to sources (articles, presentations, etc.).

© Laesus De Liro

The occurrence of these diseases is associated with changes in the DNA of mitochondria. The mitochondrial DNA genome has been completely deciphered. It contains ribosomal RNA genes, 22 tRNAs, and 13 polypeptides involved in oxidative phosphorylation reactions. Most mitochondrial proteins are encoded by nuclear DNA genes, are translated in the cytoplasm, and then enter the mitochondria. Mitochondrial DNA is maternally inherited. The cytoplasm of the egg contains thousands of mitochondria, while the mitochondria of the sperm do not end up in the zygote. Therefore, males inherit mtDNA from their mothers but do not pass it on to their offspring.

Each mitochondria contains 10 or more DNA molecules. Usually, all copies of mtDNA are identical. Sometimes, however, mutations occur in mtDNA that can be transmitted to both daughter mitochondria and daughter cells.

Clinically, mutations can manifest themselves in the form of various symptoms in any organ or tissue and at any age. The most energy-dependent, and therefore vulnerable, are the brain, heart, skeletal muscles, endocrine system, liver. Lesions of the nervous system are usually accompanied by convulsions, impaired coordination (ataxia), decreased intelligence, neurosensory deafness.

Examples of hereditary diseases: Leber's optic disc atrophy (acute loss of central vision, can occur at any age), mitochondrial encephalomyopathy, myoclonic epilepsy syndrome and torn muscle fibers.

Multifactorial diseases

They occur in individuals with an appropriate combination of predisposing alleles, there is a polymorphism of clinical signs, diseases manifest themselves at any age, any system or organ can be involved in the pathological process. Examples: hypertension, atherosclerosis, peptic ulcer, schizophrenia, epilepsy, glaucoma, psoriasis, bronchial asthma, etc.

Peculiarities:

High frequency of occurrence in the population

Existence of various clinical forms

The dependence of the degree of risk for the relatives of the patient:

The rarer the disease in the population, the higher the risk for relatives of the proband

The more pronounced the disease in the proband, the higher the risk of the disease in his relative

The risk for relatives of the proband will be higher if there is another sick blood relative.

Medical genetic counseling

This is one of the types of specialized medical care for the population. Geneticists, as well as other specialists (obstetricians, pediatricians, endocrinologists, neuropathologists) work in the consultation. The main tasks of the consultation:

Assisting doctors in diagnosing a hereditary disease

Determining the probability of having a child with a hereditary pathology

Explanations to parents about the meaning of genetic risk

Stages of counseling:

1. Examination of the patient and diagnosis of a hereditary disease. Various methods are used for this: cytogenetic, biochemical, DNA diagnostics. Indications for counseling are:

Established or suspected hereditary disease in the family

Birth of a child with malformations

Repeated spontaneous abortions, stillbirths, infertility

Lagging children in mental and physical development

Violation of sexual development

consanguineous marriages

Possible exposure to teratogens in the first 3 months of pregnancy

2. Determining the risk of having a sick child. When determining risk, the following situations are possible:

a) in case of monogenically inherited diseases, the calculation of risk is based on the laws of G. Mendel. This takes into account the genotype of the parents and the features of the expression of the gene (penetrance and expressivity).

b) for polygenically inherited diseases (diseases with a hereditary predisposition), special tables are used to calculate the risk, and the following features are taken into account:

The rarer the disease in the population, the higher the risk for the relatives of the proband

The more pronounced the disease in the proband, the higher the risk of the disease in his relatives.

The risk for relatives of the proband will be higher if there is another sick blood relative

c) sporadic cases of the disease: a sick child is born to phenotypically healthy parents, while there are no data in a similar pathology in relatives. The reasons:

Generative mutations in one of the parents or somatic mutations in the early stages of embryonic development

The transition of a recessive gene to a homozygous state

Concealment by one of the parents of family pathology.

3. Conclusion of consultation and advice to parents. A genetic risk of up to 5% is considered low and is not a contraindication for childbearing. The risk is from 6 to 20% - is defined as medium and is regarded as a contraindication to conception or as an indication for termination of pregnancy. Regardless of the degree of risk, prenatal diagnosis is advisable.

Prenatal (prenatal) diagnosis.

Many diseases can be detected even before the birth of a child. If serious diseases are detected in the fetus, the doctor offers the family an artificial termination of pregnancy. The final decision on this issue must be made by the family. Prenatal diagnostic methods include:

1. Biopsy of chorionic villi. Produced at 7-9 weeks of pregnancy. It serves to detect chromosomal defects, enzyme activity in order to diagnose hereditary metabolic diseases and DNA diagnostics.

2. Amniocentesis (taking amniotic fluid with cells contained in it). Produced from 12-14 weeks of pregnancy.

3. Cordocentesis (blood sampling from the umbilical vessels) is performed at 20-25 weeks of gestation and is used for the same purposes.

4. Maternal blood test. Detection of α-fetoprotein (a protein that is produced by the liver of the fetus and penetrates through the placental barrier into the mother's blood). An increase in it several times at the 16th week of pregnancy may indicate neural tube defects. A decrease in its concentration in relation to the norm may indicate Down syndrome.

5. An ultrasound examination of the fetus is performed at all stages of pregnancy. Ultrasound examination is the main method of visual determination of fetal malformations and the state of the placenta. Ultrasound examination is recommended for all women at least 2 times during pregnancy.

There are a large number of chronic diseases, one of the pathogenetic links of which is secondary mitochondrial deficiency. Their list is far from complete and is expanding to this day.

All these disorders are polymorphic, may have varying degrees of severity and be of interest to medical specialists in various fields - neuropathologists, cardiologists, neonatologists, nephrologists, surgeons, urologists, otorhinolaryngologists, pulmonologists, etc.

According to our data, at least a third of all disabled children in the symptom complex of their diseases have signs of a polysystemic disorder of cellular energy. It should be noted that in recent years the number of children with diseases accompanied by a high probability of tissue hypoxia has significantly increased.

Studies recently conducted at the Moscow Research Institute of Pediatrics and Pediatric Surgery in children admitted to a genetic clinic with undifferentiated disorders of physical and neuropsychic development showed that half of them had disturbances in cellular energy exchange. For the first time, employees of this institute discovered the presence of mitochondrial disorders in such pathologies in children: connective tissue diseases (Marfan and Ehlers-Danlos syndromes), tuberous sclerosis, a number of non-endocrine syndromes accompanied by growth retardation (osteochondrodysplasia, Aarskog syndrome, Silver-Russell syndrome, etc.), the influence of mitochondrial deficiency on the course of a number of cardiological, hereditary, surgical and other diseases was revealed. Together with the staff of the Smolensk Medical Academy, a decompensating mitochondrial insufficiency was described in type 1 diabetes mellitus in children with a disease period of more than 5 years.

Of particular note are polysystemic mitochondrial dysfunctions caused by ecopathogenic factors. Among the latter are both well-known (for example, carbon monoxide, cyanides, heavy metal salts) and relatively recently described (primarily side effects of a number of drugs - azidothymidine, valproates, aminoglycosides, and some others). In addition, the same group includes mitochondrial dysfunctions caused by a number of nutritional disorders (primarily a deficiency of B vitamins).

Finally, it should be mentioned separately that, according to many researchers, an increase in the number of mitochondrial dysfunctions is, if not the main, then one of the most important mechanisms of aging. At the International Symposium on Mitochondrial Pathology, held in Venice in 2001, the discovery of specific mitochondrial DNA mutations that appear with aging was reported. These mutations are not found in young patients, and in the elderly they are determined in various cells of the body with a frequency of over 50%.

Pathogenesis.

A decrease in oxygen delivery to the nerve cell under conditions of acute ischemia leads to a number of regulatory functional and metabolic changes in mitochondria, among which disturbances in the state of mitochondrial enzyme complexes (MFCs) play a leading role and lead to suppression of aerobic energy synthesis. The general response of the body to acute oxygen deficiency is characterized by the activation of urgent regulatory compensatory mechanisms. In a neuronal cell, cascade mechanisms of intracellular signal transduction are activated, which are responsible for gene expression and the formation of adaptive traits. Such activation appears already after 2-5 minutes of oxygen starvation and proceeds against the background of a decrease in respiration associated with the suppression of MFC-1. Confirmation of the involvement of intracellular signaling systems in adaptive processes, which are necessary for the formation of genome-dependent adaptive reactions, is the activation of protein kinases - the final links of these systems, the opening of the mito-KATP channel, the enhancement of the ATP-dependent K+ transport associated with it, and increased generation of H2O2.

At this stage of adaptive reactions, the key role is assigned to the families of the so-called early genes, the products of which regulate the expression of late-acting genes. To date, it has been established that in the brain these genes include NGFI-A, c-jun, junB, c-fos, which play an important role in the processes of neuronal plasticity, learning, survival/death of neurons. In the case when preconditioning had a protective effect and corrected the disorders caused by severe hypoxia in hypoxia-sensitive brain structures, an increase in the expression of mRNA of all these genes, as well as mRNA of mitochondrial antioxidant genes, was observed.

A longer stay in conditions of reduced oxygen content is accompanied by a transition to a new level of regulation of oxygen homeostasis, which is characterized by economization of energy metabolism (a change in the kinetic properties of oxidative metabolism enzymes, which is accompanied by an increase in the efficiency of oxidative phosphorylation, the emergence of a new population of small mitochondria with a set of enzymes that allow them to work in this new mode). In addition, under these conditions, adaptation to hypoxia at the cellular level is closely associated with the transcriptional expression of hypoxia-induced late-acting genes that are involved in the regulation of multiple cellular and systemic functions and are necessary for the formation of adaptive traits. It is known that at low oxygen concentrations, this process is primarily controlled by a specific transcription factor induced by hypoxia in all tissues (HIF-1). This factor, discovered in the early 1990s, functions as the main regulator of oxygen homeostasis and is the mechanism by which the body, in response to tissue hypoxia, controls the expression of proteins responsible for the mechanism of oxygen delivery to the cell, i.e. regulates adaptive cell responses to changes in tissue oxygenation.

Currently, more than 60 direct target genes have been identified for it. All of them contribute to the improvement of oxygen delivery (erythropoiesis, angiogenesis), metabolic adaptation (glucose transport, increased glycolytic ATP production, ion transport) and cell proliferation. HIF-1 regulated products act at different functional levels. The end result of this activation is an increase in O2 entry into the cell.

Identification and cloning of HIF-1 made it possible to establish that it is a heterodimeric redox-sensitive protein consisting of two subunits: an inducibly expressed oxygen-sensitive HIF-1b subunit and a constitutively expressed HIF-1c subunit (aryl hydrocarbon receptor nuclear translocator). -- ARNT). Heterodimerizing with the arylcarboxylic receptor (AHR), it forms a functional dioxin receptor. Other proteins of the HIF-1b family are also known: HIF-2b, HIF-3b. All of them belong to the family of basic proteins containing in the amino acid terminal part of each subunit the basic helix-loop-helix (bHLH) domain, which is characteristic of a wide variety of transcription factors and is necessary for dimerization and binding. DNA.

HIF-1b consists of 826 amino acid residues (120 kD) and contains two transcription domains at the C-terminal end. Under normoxic conditions, its synthesis occurs at a low rate and its content is minimal, since it undergoes rapid ubiquitination and degradation by proteasomes. This process depends on the interaction of the primary structure of HIF-1b and its specific oxygen-dependent degradation domain (ODDD) with the von Hippel Lindau (VHL) protein, which is widespread in tissues, a tumor growth suppressor that acts as a protein ligase. .

The molecular basis for such regulation is the O2-dependent hydroxylation of its two proline residues P402 and P564, which are part of the structure of HIF-1b, by one of three enzymes collectively known as “proteins of the prolyl hydroxylase domain (PHD)”, or “HIF-1b-prolylyl hydroxylase ”, which is necessary for the binding of HIF-1b to the VHL protein. Obligatory components of the process are also β-ketoglutarate, vitamin C and iron. Along with this, hydroxylation of the asparagine residue in the C-terminal transactivation domain (C-TAD) occurs, which leads to the suppression of the transcriptional activity of HIF-1b. After hydroxylation of the proline residues in ODDD and the asparagine residue, HIF-1b binds to the VHL protein, which makes this subunit of proteasomal degradation available.

Under conditions of a sharp oxygen deficiency, the oxygen-dependent process of hydroxylation of prolyl residues, which is characteristic of normoxia, is suppressed. Because of this, VHL cannot bind to HIF-1b, its degradation by proteasomes is limited, which makes its accumulation possible. In contrast, p300 and CBP can bind to HIF-1b, since this process does not depend on asparaginyl hydroxylation. This ensures the activation of HIF-1b, its translocation to the nucleus, dimerization with HIF-1b, leading to conformational changes, the formation of a transcriptional active complex (HRE), which triggers the activation of a wide range of HIF-1-dependent target genes and the synthesis of protective adaptive proteins in response. for hypoxia.

The above mechanisms of intracellular signal transduction occur in the cell during its adaptation to hypoxia. In the case when disadaptation sets in, a significant concentration of ROS accumulates in the cell, and the processes of its apoptotic death are activated.

Among the former are, in particular, the transfer of phosphatidylserine to the outer membrane layer and DNA fragmentation under the action of ROS and NO. In this membrane, phosphatidylserine is usually present only in the inner lipid layer. Such an asymmetric distribution of this phospholipid is due to the action of a special transport ATPase that transfers phosphatidylserine from the outer lipid layer of the plasma membrane to the inner one. This ATPase is either inactivated by the oxidized form of phosphatidylserine or simply "does not recognize" the oxidized phospholipid. That is why the oxidation of phosphatidylserine by ROS leads to its appearance in the outer layer of the plasma membrane. Apparently, there is a special receptor that detects phosphatidylserine in the outer lipid layer. It is assumed that this receptor, by binding phosphatidylserine, sends a signal of apoptosis into the cell.

Phosphatidylserine plays a key role in the so-called forced apoptosis caused by a certain type of leukocyte. A cell with phosphatidylserine in the outer layer of the cell membrane is "recognized" by these leukocytes, which initiate its apoptosis. One of the apoptogenic mechanisms used by leukocytes is that leukocytes begin to secrete proteins perforin and granzymes into the intercellular space near the target cell. Perforin makes holes in the outer membrane of the target cell. Granzymes enter the cell and trigger apoptosis in it.

Another method used by the leukocyte to force the target cell to enter apoptosis is to bombard it with superoxide produced outside the leukocyte via a special transmembrane respiratory chain of the plasma membrane. This chain oxidizes intracellular NADPH, from which electrons are transferred to flavin and then to a special cytochrome b, which can be oxidized by oxygen to release superoxide outside the leukocyte. Superoxide and other ROS formed from it oxidize the plasma membrane phosphatidylserine of the target cell, thereby enhancing the apoptotic signal sent to the cell by this phospholipid.

In addition, leukocytes include tumor necrosis factor. TNF binds to its receptor on the outer side of the plasma membrane of the target cell, which activates several parallel pathways for triggering apoptosis. In one of them, the formation of active caspase-8 from pro-caspase-8 occurs. Caspase-8 is a protease that cleaves the cytosolic Bid protein with the formation of its active form tBid (truncated Bid). tBid changes the conformation of another protein, Bax, causing the formation of a protein-permeable channel in the outer membrane of mitochondria, which leads to their exit from the intermembrane space into the cytosol.

The diversity of pathways of ROS-dependent apoptosis is illustrated in Fig. 1. The true picture, in all likelihood, is even more complex, since in addition to TNF there are other extracellular inducers of apoptosis (cytokines), each acting through its own receptor. In addition, there are anti-apoptotic systems that oppose pro-apoptotic systems. Among them are proteins of the Bcl-2 type, which inhibit the proapoptotic activity of Bax; the already mentioned caspase inhibitors (IAP); protein NFkB (nuclear factor kB) induced by TNF. NFkB includes a group of genes, among which are those encoding superoxide dismutase and other antioxidant and anti-apoptotic proteins.

All these difficulties reflect the obvious circumstance that for a cell "the decision to commit suicide" is an extreme measure when all other possibilities to prevent its erroneous actions have been exhausted.

Taking into account the above, we can imagine the following scenario of events designed to protect the body from ROS generated by mitochondria. Formed in mitochondria, ROS cause the opening of a pore and, as a consequence, the release of cytochrome C into the cytosol, which immediately activates additional antioxidant mechanisms, and then mitoptosis. If only a small part of the intracellular population of mitochondria goes into mitoptosis, the concentrations of cytochrome C and other mitochondrial proapoptotic proteins in the cytosol do not reach the values ​​necessary to activate apoptosis. If more and more mitochondria become ROS superproducers and “open kingstones”, these concentrations increase and apoptosis of the cell containing many defective mitochondria begins. As a result, the tissue is cleared of cells whose mitochondria produce too much ROS.

Thus, we can speak of mitochondrial dysfunction as a new pathobiochemical mechanism of a wide range of neurodegenerative disorders. Currently, two types of mitochondrial dysfunction are distinguished - primary, as a result of a congenital genetic defect, and secondary, arising under the influence of various factors: hypoxia, ischemia, oxidative and nitrosative stress, and expression of pro-inflammatory cytokines. In modern medicine, the doctrine of polysystemic disorders of cellular energy metabolism, the so-called mitochondrial pathology, or mitochondrial dysfunction, occupies an increasingly important place.

Mitochondrial dysfunctions are a heterogeneous group of pathologies caused by genetic, biochemical and structural and functional defects of mitochondria with impaired cellular and tissue respiration. The classification of mitochondrial dysfunction has its own history. One of the first was a scheme based on biochemical defects in metabolism. The systematization by clinical syndromes was also not deep enough, among them the following were previously distinguished:

• 1) syndromes of established mitochondrial nature;
• 2) syndromes of presumably mitochondrial nature;
• 3) syndromes are consequences of mitochondrial pathology.

The first mention of a disease associated with a defect in mitochondria refers to 1962: R. Luft et al. described a case of a disease in which there was a violation of the conjugation of respiration and phosphorylation in the mitochondria of skeletal muscles in a patient with non-thyroidal hypermetabolism. In subsequent years, the clinical, biochemical and morphological aspects of mitochondrial encephalomyopathies were described. The use of modified Gomori staining played an important role in the development of this direction, with the help of which it was possible to detect fibers with altered mitochondria in skeletal muscles - the so-called ragged-red fibers (RRF).

Later, with the discovery of the mitochondrial genome and mDNA or nuclear DNA mutations, it was possible to apply the genetic principle of classification for primary, congenital mitochondrial dysfunction - first in a simplified form, then in a more complicated one. The key area of ​​mitochondrial pathology is hereditary syndromes, which are based on mutations in the genes responsible for mitochondrial proteins (Kearns-Sayre syndromes, MELAS, MERRF, Pearson, Barth, etc.). Mitochondrial dysfunctions are manifested by a wide range of clinical symptoms. These mutations may involve tRNA, rRNA, or structural genes and may be expressed biochemically as defects in the entire electron transport chain or as defects in individual enzymes.

Throughout the 1990s, the identification of many mitochondrial defects that cause clinically very different disorders baffled clinicians regarding the diagnosis of heterogeneous and complex syndromes characterized by the following features:

• - skeletal muscles: low exercise tolerance, hypotension, proximal myopathy, including facial and pharyngeal muscles, ophthalmoparesis, ptosis;
• - heart: cardiac arrhythmias, hypertrophic myocardiopathy;
• - CNS: optic nerve atrophy, retinopathy pigmentosa, myoclonus, dementia, stroke-like episodes, mental disorders;
• - peripheral nervous system: axonal neuropathy, impaired motor activity of the gastrointestinal tract;
• -- endocrine system: diabetes, hypoparathyroidism, impaired exocrine pancreatic function, short stature.

Since primary mitochondrial dysfunction manifests itself in a person with a number of different symptoms, clinicians have tried to combine some groups of the most common combinations of symptoms into syndromes:

• MELAS - Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes).
• CPEO / PEO - External Ophtalmoplegia, Ophtalmoplegia plus syndrome (ophthalmoplegia associated with damage to the oculomotor muscles, ophthalmoplegia plus syndrome).
• KSS - Kearns - Sayre Syndrome - retinopathy, proximal muscle weakness, cardiac arrhythmia and ataxia (retinopathy, proximal muscle weakness, arrhythmia, ataxia).
• · MERRF -- Myoclonic Epilepsy associated with Ragged Red Fibres.
• LHON - Leber Hereditary Optic Neuropathy (congenital neuropathy of the optic nerve).
• · Leig syndrome -- infantile subacute necrotizing encephalopathy (infantile subacute necrotizing encephalopathy).
• · NAPR -- Neuropathy, Ataxia and Pigmentary Retinopathy (neuropathy, ataxia and pigmentary retinopathy).

Mitochondrial diseases are a group of hereditary pathologies resulting from disorders of cellular energy, characterized by a polymorphism of clinical manifestations, expressed in the predominant lesion of the central nervous system and the muscular system, as well as other organs and systems of the body.

An alternative definition of mitochondrial pathology says that this is a large group of pathological conditions caused by genetic, structural and biochemical defects in mitochondria, impaired tissue respiration and, as a result, insufficient energy metabolism.

As A. Munnich points out, "mitochondrial diseases can cause any symptom, in any tissue, at any age, with any type of inheritance."

Mitochondrial respiratory chains are the main final pathway of aerobic metabolism. Therefore, mitochondrial pathology is often referred to as "mitochondrial respiratory chain diseases" (MRDC); This is a relatively new class of diseases.

Historical aspects of mitochondrial pathology

R. Luft et al. (1962) found a relationship between muscle weakness and disturbances in the processes of oxidative phosphorylation in muscle tissue. S. Nass and M. Nass (1963) discovered the existence of their own genetic apparatus of mitochondria (several copies of the ring chromosome were found). In 1960-1970. the concept of mitochondrial diseases appeared, that is, a pathology etiologically mediated by mitochondrial dysfunction. In the 1980s accurate molecular genetic evidence of the mitochondrial nature of a number of diseases (Leber's disease, Pearson's syndrome) was obtained.

Etiopathogenetic aspects of mitochondrial pathology

Depending on the presence of the main metabolic defect, it is customary to consider four main groups of mitochondrial diseases: 1) disorders of pyruvate metabolism; 2) defects in fatty acid metabolism; 3) violations of the Krebs cycle; 4) defects in electron transport and oxidative phosphorylation (OXPHOS).

The causes of mitochondrial pathology are mutations in genes encoding proteins involved in energy metabolism in cells (including subunits of the pyruvate dehydrogenase complex, Krebs cycle enzymes, components of the electron transport chain, structural proteins of the electron transport chain (ETC), mitochondrial inner membrane transporters, regulators of mitochondrial nucleotide pool, as well as factors interacting with mitochondrial DNA (mtDNA).

Mitochondrial disorders are associated with a large number of diseases that are not primary mitochondrial cytopathies. Nevertheless, in these diseases, mitochondrial dysfunctions make a significant contribution to the pathogenesis and clinical manifestations of diseases. The diseases described can be metabolic, degenerative, inflammatory, congenital/acquired malformations, and neoplasms.

The mitochondrion is an organelle that is present in almost every cell, with the exception of mature red blood cells. That is why mitochondrial diseases can affect any systems and organs of the human body. In this regard, it is more correct to call these conditions "mitochondrial cytopathies".

The main features of mitochondrial cytopathies include a pronounced polymorphism of clinical symptoms, a multisystemic nature of the lesion, variability in the course, progression, and inadequate response to the therapy used.

The respiratory chain is localized on the inner membrane of mitochondria and includes five multienzyme complexes, each of which, in turn, consists of several dozen subunits. Mitochondrial DNA codes for only 13 of the respiratory chain protein subunits, 2 mtRNA protein subunits, and 22 mitochondrial transfer RNAs (tRNAs). The nuclear genome codes for over 90% of mitochondrial proteins.

The end result of oxidative phosphorylation occurring in 1-γ complexes is the production of energy (ATP). Adenosine triphosphate is the main source of energy for cells.

Mitochondrial DNA interacts closely with nuclear DNA (nDNA). In each of the 5 respiratory complexes, most of the subunits are encoded by nDNA, not mtDNA. Complex I consists of 41 subunits, of which 7 are encoded by mtDNA and the rest by nDNA. Complex II has only 4 subunits; most of them are encoded by nuclear DNA. Complex III is represented by ten subunits; mtDNA coding - 1, nDNA - 9. Complex IV has 13 subunits, of which 3 are encoded by mtDNA, and 10 by nDNA. Complex V includes 12 subunits, mtDNA coding - 2, nDNA - 10.

Violations of cellular energy lead to polysystemic diseases. First of all, the most energy-dependent organs and tissues suffer: the nervous system (encephalopathy, polyneuropathy), the muscular system (myopathies), the heart (cardiomyopathies), kidneys, liver, endocrine system and other organs and systems. Until recently, all these diseases were defined under numerous masks of other nosological forms of pathology. To date, more than 200 diseases have been identified that are caused by mutations in mitochondrial DNA.

Mitochondrial diseases can be caused by pathology of both the mitochondrial and nuclear genomes. As pointed out by P. F. Chinnery et al. (2004) and S. DiMauro (2004), mtDNA mutations were detected in 1 case per 8,000 population, and the prevalence of mitochondrial diseases is about 11.5 cases per 100,000 population.

Each cell contains from several hundred to several thousand organelles - mitochondria, containing from 2 to 10 circular molecules of mitochondrial DNA, capable of replication, transcription and translation, and independently of nuclear DNA.

Genetic aspects of mitochondrial pathology

Mitochondrial genetics differs from classical Mendelian genetics in three important aspects: 1) maternal inheritance (the entire cytoplasm, together with the organelles in it, is received by the offspring together with the egg); 2) heteroplasmy - the simultaneous existence in the cell of normal (wild) and mutant types of DNA; 3) mitotic segregation (both types of mtDNA in the process of cell division can be distributed randomly between daughter cells).

Mitochondrial DNA accumulates mutations more than 10 times faster than the nuclear genome, since it lacks protective histones and its environment is extremely rich in reactive oxygen species, which are a by-product of metabolic processes occurring in mitochondria. The proportion of mutant mtDNA must exceed a critical threshold level before cells begin to exhibit biochemical abnormalities of the mitochondrial respiratory chains (threshold effect). The percentage level of mutant mtDNA can vary among individuals within families, as well as in organs and tissues. This is one of the explanations for the variability of the clinical picture in patients with mitochondrial dysfunctions. The same mutations can cause different clinical syndromes (for example, A3243G mutation - encephalopathy with stroke-like paroxysms - MELAS syndrome, as well as chronic progressive external ophthalmoplegia, diabetes mellitus). Mutations in different genes can cause the same syndrome. The classic example of such a situation is the MELAS syndrome.

Varieties of mitochondrial pathology

If we list the main mitochondrial diseases, then they will include the following: mitochondrial neurogastrointestinal encephalopathy (MNGIE), multiple mitochondrial DNA deletion syndrome, lipid myopathy with normal carnitine levels, carnitine palmitoyltransferase deficiency, mitochondrial diabetes mellitus, Alpers-Huttenlocher disease, Kearns-Sayre syndrome , Leber's disease (LHON), Wolfram's syndrome, MEMSA syndrome, Pearson's syndrome, SANDO syndrome, MIRAS syndrome, MELAS syndrome, MERRF syndrome, SCAE syndrome, NARP syndrome, Barth's syndrome, CPEO syndrome, Lee's syndrome, etc. .

The most common clinical syndromes of mitochondrial pathology in childhood are: MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like paroxysms), MERRF syndrome (myoclonus epilepsy with torn red fibers), Kearns-Sayre syndrome (characterized by ptosis, ophthalmoplegia, retinitis pigmentosa , ataxia, impaired cardiac conduction), NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), Lee's syndrome (subacute necrotizing encephalomyelopathy), Leber's disease (hereditary optic neuropathy).

There is a large pool of diseases caused not by mutations in mitochondrial DNA, but by mutations in nuclear DNA that codes for mitochondrial function. These include the following types of pathology: Barth's disease (myopathy, cardiomyopathy, transient neutro- and thrombocytopenia), mitochondrial gastrointestinal encephalopathy (autosomal recessive multisystem disease): ptosis, ophthalmoplegia, peripheral neuropathy, gastrointestinal dysfunction leading to cachexia, leukoencephalopathy. The age of onset of the latter disease is highly variable, ranging from the neonatal period to 43 years.

Diagnosis of mitochondrial pathology

Clinical criteria for diagnosing mitochondrial diseases are relatively numerous: 1) myopathic symptom complex (exercise intolerance, muscle weakness, decreased muscle tone); 2) seizures (myoclonic or multifocal); 3) cerebellar syndrome (ataxia, intentional tremor); 4) damage to the oculomotor nerves (ptosis, external ophthalmoplegia); 5) polyneuropathy; 6) stroke-like paroxysms; 7) migraine-like headaches; 8) craniofacial dysmorphia; 9) dysmetabolic manifestations (vomiting, episodes of lethargy, coma); 10) respiratory disorders (apnea, hyperventilation, tachypnea); 11) damage to the heart, liver, kidneys; 12) progressive course of the disease.

The following clinical criteria are used in the diagnosis of mitochondrial diseases: 1) signs of connective tissue damage (hypermobility syndrome, skin hyperelasticity, posture disorders, etc.); 2) neurodegenerative manifestations, leukopathy during magnetic resonance imaging (MRI) of the brain; 3) repeated episodes of impaired consciousness or unexplained episodes of vomiting in newborns; 4) unexplained ataxia; 5) mental retardation without specific reasons; 6) burdened family history; 7) a sudden deterioration in the child's condition (convulsions, vomiting, respiratory disorders, lethargy, weakness, muscle tone disorders - more often muscle hypotension, coma, lethargy; liver and kidney damage that is not amenable to conventional therapy).

Laboratory (biochemical) studies are aimed primarily at identifying lactic acidosis and / or pyruvate acidosis in patients. It should be remembered that normal lactic acid levels do not exclude the presence of mitochondrial disease. Other biochemical parameters investigated in cases of suspected mitochondrial pathology include blood and urine ketone bodies, plasma acylcarnitines, and blood and urine organic acids and amino acids.

M. V. Miles et al. (2008) proposed to evaluate the content of muscle coenzyme Q10 in children with a defect in mitochondrial respiratory chain enzymes.

Cytomorphodensitometric studies make it possible to evaluate the activity of lymphocyte mitochondria (decrease in number, increase in volume, decrease in activity).

Of the instrumental studies (in addition to neuroimaging methods), a skeletal muscle biopsy is used with specific histochemical reactions to identify the phenomenon of "ragged red fibers" (ragged red fibers - RRF) in the resulting biopsy. Syndromes with "torn red fibers" are the following: MELAS, MERRF, KSS, PEO (progressive external ophthalmoplegia), and Pearson's syndrome. Syndromes without RRF: Leigh's disease, NARP, LHON (Leber's hereditary optic neuropathy).

Genetic research methods are reduced to determining the most frequent mutations and mitochondrial DNA sequencing.

Treatment of mitochondrial pathology

Therapy for mitochondrial diseases, unfortunately, has not been developed. From the standpoint of evidence-based medicine, it is believed that there is no effective treatment for this representative group of diseases. Nevertheless, in various countries of the world, pharmacological agents and biologically active substances are used to normalize metabolism and provide adequate energy for mitochondria.

In MELAS syndrome, treatment should be aimed at treating seizures, endocrine disorders, and eliminating the consequences of a stroke.

P. Kaufmann et al. (2006) indicate that since lactate levels often correlate with the severity of neurological manifestations, it is reasonable to use dichloroacetate to reduce lactate levels. In our country, dimethyloxobutylphosphonyl dimethylate (Dimephosphone) is used for a similar purpose.

In the studies of Japanese authors Y. Koga et al. (2002, 2005, 2006, 2007), intravenous administration of L-arginine (NO precursor) was used with good effect to stimulate vasodilation in the acute period of stroke, as well as oral administration to reduce the severity of subsequent episodes.

Among the drugs used in the treatment of mitochondrial pathology are the following: vitamin B 1 (thiamine) - 400 mg / day, vitamin B 2 (riboflavin) - 100 mg / day, vitamin C (ascorbic acid) - up to 1 g / day, vitamin E (tocopherol) - 400 IU / day, nicotinamide (niacin) - up to 500 mg / day, coenzyme Q 10 - from 90 to 200 mg / day, L-carnitine - from 10 mg to 1-2 g / day, succinic acid - from 25 mg to 1.5 g / day, Dimephosphone 15% - 1.0 ml per 5 kg of body weight. Cytochrome C (intravenously), Reamberin (intravenously) and Cytoflavin (intravenously and orally) are also used.

Other means of pharmacotherapy are corticosteroids, mineralocorticoids (with the development of adrenal insufficiency), anticonvulsants - with convulsions / epilepsy (excluding valproic acid and its derivatives, limiting the use of barbiturates). In our observations, the most effective anticonvulsant therapy was the use of levetiracetam (Keppra), topiramate (Topamax) or their combinations.

Neurodietology in mitochondrial pathology

The main principle of the diet in mitochondrial pathology is the restriction of nutrients that have a negative effect on metabolic mechanisms - until the formation of a metabolic block (the diet is simultaneously enriched with other components at a normal or elevated level). This therapeutic strategy has been called "going around the block". An important exception in this regard is the group of mitochondrial disorders associated with pyruvate metabolism (insufficiency of the pyruvate dehydrogenase complex with concomitant carbohydrate/glycogen/amino acid disorders). However, the ketogenic diet and other types of high-fat diets are recommended.

Substances that are food cofactors are widely used (coenzyme Q 10, L-carnitine, acetyl-L-carnitine, vitamin B 2, ascorbic acid, vitamin E, vitamin B 1, nicotinamide, vitamin B 6, vitamin B 12, biotin, folic acid , vitamin K, α-lipoic acid, succinic acid, Se) . It is recommended to avoid individual nutritional factors that induce an exacerbation of mitochondrial disease (starvation, consumption of fats, proteins, sucrose, starch, alcohol, caffeine, monosodium glutamate; quantitative eating disorders and inadequate intake of food energy). If necessary, clinical nutrition is provided (enteral, parenteral, gastrostomy).

The timely diagnosis of mitochondrial diseases, the search for clinical and paraclinical criteria for these diseases at the preliminary, pregenetic stage are extremely important. This is necessary to select adequate metabolic therapy and prevent deterioration or disability in patients with these rare diseases.

C. S. Chi (2015) emphasizes that the confirmation or exclusion of mitochondrial pathology remains fundamental in pediatric practice, especially when the clinical signs of the disease are not specific, which requires a follow-up approach to assessing symptoms and biochemical parameters.

Literature

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11. Kaufmann P., Engelstad K., Wei Y., Jhung S., Sano M. C., Shungu D. C., Millar W. S., Hong X., Gooch C. L., Mao X., Pascual J. M., Hirano M., Stacpoole P. W., DiMauro S., De Vivo D.C. Dichloracetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial // Neurology. 2006 Vol. 66(3): 324-330.
12. Federal Guidelines for the Use of Medicines (formulary system). Issue. XVI. M.: Ekho, 2015. 540.
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14. Koga Y., Akita Y., Nishioka J., Yatsuga S., Povalko N., Tanabe Y., Fujimoto S., Matsuishi T. L-arginine improves the symptoms of strokelike episodes in MELAS // Neurology. 2005 Vol. 64(4): 710-712.
15. Koga Y., Akita Y., Junko N., Yatsuga S., Povalko N., Fukiyama R., Ishii M., Matsuishi T. Endothelial dysfunction in MELAS improved by L-arginine supplementation // Neurology. 2006 Vol. 66(11): 1766-1769.
16. Koga Y., Akita Y., Nishioka J., Yatsuga S., Povalko N., Katayama K., Matsuishi T. MELAS and L-arginine therapy // Mitochondrion. 2007 Vol. 7(1-2): 133-139.
17. Rai P. K., Russell O. M., Lightowlers R. N., Turnbull D. M. Potential compounds for the treatment of mitochondrial disease // Br. Med. Bull. 2015. Nov 20. pii: ldv046. .
18. Finsterer J., Bindu P.S. Therapeutic strategies for mitochondrial disorders // Pediatr. Neurol. 2015. Vol. 52(3): 302-313.
19. Studenikin V. M., Goryunova A. V., Gribakin S. G., Zhurkova N. V., Zvonkova N. G., Ladodo K. S., Pak L. A., Roslavtseva E. A., Stepakina E. I., Studenikina N. I., Tursunkhuzhaeva S. Sh., Shelkovsky V. I. Mitochondrial encephalopathies. Chapter 37. In the book: Neurodietology of childhood (collective monograph) / Ed. Studenikina V. M. M.: Dynasty, 2012. S. 415-424.
20. Chi C.S. Diagnostic approach in infants and children with mitochondrial diseases // Pediatr. neonatol. 2015. Vol. 56(1): 7-18.

V. M. Studenikin* , 1 ,doctor of medical sciences, professor, academician of the Russian Academy of Natural Sciences
O. V. Globa**,Candidate of Medical Sciences

* GOU VPO RNIMU them. N. I. Pirogov Ministry of Health of the Russian Federation, Moscow
** GOU VPO PMGMU them. I. M. Sechenov Ministry of Health of the Russian Federation, Moscow

Mitochondrial diseases are a heterogeneous group of hereditary diseases that are caused by structural, genetic or biochemical defects in mitochondria, leading to disruption of energy functions in the cells of eukaryotic organisms. In humans, mitochondrial diseases primarily affect the muscular and nervous systems.

ICD-9	277.87
MeSH	D028361
DiseasesDB	28840

General information

Mitochondrial diseases as a separate type of pathology were identified at the end of the 20th century after the discovery of mutations in the genes responsible for the synthesis of mitochondrial proteins.

Mutations in mitochondrial DNA discovered in the 1960s and the diseases caused by these mutations are more studied than diseases caused by disturbances in nuclear-mitochondrial interactions (nuclear DNA mutations).

To date, at least 50 diseases known to medicine are associated with mitochondrial disorders. The prevalence of these diseases is 1:5000.

Kinds

Mitochondria are unique cellular structures that have their own DNA.

According to many researchers, mitochondria are the descendants of archaebacteria that have turned into endosymbionts (microorganisms that live in the body of the "owner" and benefit him). As a result of introduction into eukaryotic cells, they gradually lost or transferred to the nucleus of the eukaryotic host a large part of the genome, and this is taken into account in the classification. The participation of a defective protein in the biochemical reactions of oxidative phosphorylation is also taken into account, which makes it possible to store energy in the form of ATP in mitochondria.

There is no single generally accepted classification.

The generalized modern classification of mitochondrial diseases distinguishes:

• Diseases caused by mutations in mitochondrial DNA. Defects can be caused by point mutations in proteins, tRNAs or rRNAs (usually maternally inherited), or structural rearrangements - sporadic (irregular) duplications and deletions. These are primary mitochondrial diseases, which include pronounced hereditary syndromes - Kearns-Sayre syndrome, Leber syndrome, Pearson syndrome, NAPR syndrome, MERRF syndrome, etc.
• Diseases caused by defects in nuclear DNA. Nuclear mutations can disrupt the functions of mitochondria - oxidative phosphorylation, operation of the electron transport chain, utilization or transport of substrates. Also, mutations in nuclear DNA cause defects in enzymes that are necessary to ensure a cyclic biochemical process - the Krebs cycle, which is a key step in the respiration of all oxygen-using cells and the intersection center of metabolic pathways in the body. This group includes gastrointestinal mitochondrial disease, Luft syndrome, Friedrich's ataxia, Alpers syndrome, connective tissue diseases, diabetes, etc.
• Diseases that arise as a result of disorders in nuclear DNA and secondary changes in mitochondrial DNA caused by these disorders. Secondary defects are tissue-specific deletions or duplications of mitochondrial DNA and a decrease in the number of copies of mitochondrial DNA or their absence in tissues. This group includes liver failure, De Toni-Debre-Fanconi syndrome, etc.

Reasons for development

Mitochondrial diseases are caused by defects in organelles located in the cell cytoplasm - mitochondria. The main function of these organelles is the production of energy from the products of cellular metabolism entering the cytoplasm, which occurs due to the participation of about 80 enzymes. The released energy is stored in the form of ATP molecules, and then converted into mechanical or bioelectrical energy, etc.

The causes of mitochondrial diseases are a violation of the production and accumulation of energy due to a defect in one of the enzymes. First of all, with chronic energy deficiency, the most energy-dependent organs and tissues suffer - the central nervous system, the heart muscle and skeletal muscles, the liver, kidneys and endocrine glands. Chronic energy deficiency causes pathological changes in these organs and provokes the development of mitochondrial diseases.

The etiology of mitochondrial diseases has its own specifics - most mutations occur in the genes of mitochondria, since redox processes are intense in these organelles and DNA-damaging free radicals are formed. In mitochondrial DNA, damage repair mechanisms are imperfect, since it is not protected by histone proteins. As a result, defective genes accumulate 10-20 times faster than in nuclear DNA.

Mutated genes are transmitted during the division of mitochondria, so even in one cell there are organelles with different genome variants (heteroplasmy). When a mitochondrial gene is mutated in humans, a mixture of mutant and normal DNA is observed in any ratio, therefore, even in the presence of the same mutation, mitochondrial diseases in humans are expressed to varying degrees. The presence of 10% defective mitochondria does not have a pathological effect.

The mutation may not manifest itself for a long time, since normal mitochondria compensate at the initial stage for the insufficiency of the function of defective mitochondria. Over time, defective organelles accumulate, and pathological signs of the disease appear. With an early manifestation, the course of the disease is more severe, the prognosis may be negative.

Mitochondrial genes are transmitted only from the mother, since the cytoplasm containing these organelles is present in the egg and is practically absent in the spermatozoa.

Mitochondrial diseases, which are caused by defects in nuclear DNA, are transmitted by autosomal recessive, autosomal dominant, or X-linked inheritance patterns.

Pathogenesis

The mitochondrial genome differs from the genetic code of the nucleus and more closely resembles that of bacteria. In humans, the mitochondrial genome is represented by copies of a small circular DNA molecule (their number ranges from 1 to 8). Each mitochondrial chromosome codes for:

• 13 proteins that are responsible for the synthesis of ATP;
• rRNA and tRNA, which are involved in protein synthesis in mitochondria.

About 70 mitochondrial protein genes are encoded by nuclear DNA genes, due to which the centralized regulation of mitochondrial functions is carried out.

The pathogenesis of mitochondrial diseases is associated with processes that occur in mitochondria:

• With the transport of substrates (organic keto acid pyruvate, which is the end product of glucose metabolism, and fatty acids). Occurs under the influence of carnitine palmitoyl transferase and carnitine.
• With the oxidation of substrates, which occurs under the influence of three enzymes (pyruvate dehydrogenase, lipoate acetyltransferase and lipoamide dehydrogenase). As a result of the oxidation process, acetyl-CoA is formed, which is involved in the Krebs cycle.
• With the tricarboxylic acid cycle (Krebs cycle), which not only occupies a central place in energy metabolism, but also supplies intermediate compounds for the synthesis of amino acids, carbohydrates and other compounds. Half of the steps in the cycle are oxidative processes that release energy. This energy is accumulated in the form of reduced coenzymes (molecules of non-protein nature).
• with oxidative phosphorylation. As a result of the complete decomposition of pyruvate in the Krebs cycle, the coenzymes NAD and FAD are formed, which are involved in the transfer of electrons to the respiratory electron transport chain (ETC). ETC is controlled by the mitochondrial and nuclear genome and carries out electron transport using four multienzyme complexes. The fifth multienzyme complex (ATP synthase) catalyzes the synthesis of ATP.

Pathology can occur both with mutations in nuclear DNA genes and with mutations in mitochondrial genes.

Symptoms

Mitochondrial diseases are characterized by a significant variety of symptoms, since different organs and systems are involved in the pathological process.

The nervous and muscular systems are the most energy-dependent, so they suffer from an energy deficit in the first place.

Symptoms of damage to the muscular system include:

• decrease or loss of the ability to perform motor functions due to muscle weakness (myopathic syndrome);
• hypotension;
• pain and painful muscle spasms (cramps).

Mitochondrial diseases in children are manifested by headache, vomiting, and muscle weakness after exercise.

Damage to the nervous system manifests itself in:

• delayed psychomotor development;
• loss of previously acquired skills;
• the presence of seizures;
• the presence of periodic occurrence of apnea and;
• repeated coma and a shift in the acid-base balance of the body (acidosis);
• gait disorders.

Adolescents have headaches, peripheral neuropathies (numbness, loss of sensation, paralysis, etc.), stroke-like episodes, pathological involuntary movements, dizziness.

Mitochondrial diseases are also characterized by damage to the sense organs, which manifest themselves in:

• atrophy of the optic nerves;
• ptosis and external ophthalmoplegia;
• cataracts, clouding of the cornea, pigmentary retinal degeneration;
• visual field defect, which is observed in adolescents;
• hearing loss or sensorineural deafness.

Signs of mitochondrial diseases are also lesions of internal organs:

• cardiomyopathy and heart block;
• pathological enlargement of the liver, violations of its functions, liver failure;
• lesions of the proximal renal tubules, accompanied by increased excretion of glucose, amino acids and phosphates;
• vomiting, pancreatic dysfunction, diarrhea, celiac disease.

There is also macrocytic anemia, in which the average size of red blood cells is increased, and pancytopenia, which is characterized by a decrease in the number of all types of blood cells.

The defeat of the endocrine system is accompanied by:

• growth retardation and violation of sexual development;
• hypoglycemia and diabetes;
• hypothalamic-pituitary syndrome with GH deficiency;
• thyroid dysfunction;
• hypothyroidism, impaired metabolism of phosphorus and calcium, and.

Diagnostics

Diagnosis of mitochondrial diseases is based on:

• Anamnesis study. Because all symptoms of mitochondrial disease are nonspecific, the diagnosis is suggested by a combination of three or more symptoms.
• Physical examination, which includes endurance and strength tests.
• Neurological examination, including testing of vision, reflexes, speech and cognitive abilities.
• Specialized samples, which include the most informative test - muscle biopsy, as well as phosphorus magnetic resonance spectroscopy and other non-invasive methods.
• CT and MRI, which can detect signs of brain damage.
• DNA diagnostics, which allows you to identify mitochondrial diseases. Previously undescribed mutations are detected by direct mtDNA sequencing.

Treatment

Effective treatments for mitochondrial diseases are being actively developed. Attention is paid to:

• Increasing the efficiency of energy metabolism with the help of thiamine, riboflavin, nicotinamide, coenzyme Q10 (shows good results in MELAS syndrome), vitamin C, cytochrome C, etc.
• Prevention of damage to mitochondrial membranes by free radicals, for which a-lipoic acid and vitamin E (antioxidants), as well as membrane protectors (citicoline, methionine, etc.) are used.

Treatment also includes creatine monohydrate as an alternative energy source, lactic acid reduction, and exercise.

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