The phenomenon of heteroplasmy determines the existence in one cell of normal mitochondria and mitochondria with impaired function. Due to the former, the cell can function for some time. If the production of energy in it falls below a certain threshold, then there is a compensatory proliferation of all mitochondria, including defective ones. Cells that consume a lot of energy are in the worst position: neurons, muscle fibers, cardiomyocytes.

Due to leakage in the respiratory chain, mitochondria constantly produce free radicals at the level of 1-2% of absorbed oxygen. The amount of production of radicals depends on the membrane potential of mitochondria, changes in which are influenced by the state of the ATP-dependent potassium channels of mitochondria. The opening of these channels entails an increase in the formation of free radicals, damage to other proteins of mitochondrial membranes and mtDNA. Mitochondrial DNA is not protected by histones and is well accessible to radicals, which is manifested in a change in the level of heteroplasmy. It is generally accepted that the presence of 10% of mitochondria with altered DNA does not affect the phenotype.

4. CLASSIFICATION AND GENERAL CHARACTERISTICS

MITOCHONDRIAL DISEASES

There is currently no single etiological classification of the Ministry of Health exists due to the uncertainty of the contribution of nuclear genome mutations to their etiology and pathogenesis. Existing classifications are based on 2 principles: localization of the mutant gene in mtDNA or nDNA and the participation of the mutant protein in oxidative phosphorylation reactions.

Etiological classification (2006) includes mitochondrial diseases associated with defects:

· mtDNA;

· nuclear DNA;

· intergenomic interactions.

Pathogenetic classification (by, 2000) subdivides mitochondrial diseases into conditioned violation of:

· carnitine cycle;

· oxidation of fatty acids;

· metabolism of pyruvate;

· Krebs cycle;

· the work of the respiratory chain;

· conjugation of oxidation and phosphorylation.

In clinical practice, combinations of common symptoms of MH are combined into syndromes.

Mitochondrial diseases - a heterogeneous group of diseases characterized by genetic and structural-biochemical defects of mitochondria, impaired tissue respiration. By origin, MH are divided into primary (hereditary) and secondary.

The causes of hereditary MZ are mutations in the mitochondrial and (or) nuclear genome .

To date, more than 200 diseases are known to be caused by mtDNA mutations.

With the accumulation of clinical and diagnostic data in different countries, it was found that in children, approximately every third hereditary metabolic disease is associated with mitochondria. According to N.G.Danilenko, (2007) the frequency of mitochondrial diseases in populations varies from 1: 5000 to 1: 35000. The minimum incidence of MH in the UK adult population is estimated as (1-3): 10,000.

The characteristics of the clinical features of the MH are presented in Table 2.

Table 2 - Clinical features of mitochondrial diseases (by, 2007)

Clinical features	Pathophysiological significance
Polysystem, multiorganism, "inexplicable" combination of symptoms from organs that are not related by origin	Damage to organs with a close "threshold" of sensitivity to impaired oxidative phosphorylation
The presence of acute episodes at the onset of the disease or in its advanced stage	« Metabolic crisis "associated with a breakdown balance between tissue needs for energy supply and the level of anaerobic respiration
Variable age at onset of symptoms (1 to 7 decades of life)	Variable level of mutant mtDNAv different tissues at different times
Worsening of symptoms with age	Increase in the number of mtDNA mutations and weakening of the intensity of oxidative phosphorylation with aging

The defeat of most systems and organs with MH can be explained by the fact that many processes occurring in the body are energy-dependent. Relative volatility of organs and tissuesin descending order: central nervous system, skeletal muscles, myocardium, organ of vision, kidneys, liver, bone marrow, endocrine system.

Neurons need a large amount of ATP for the synthesis of neurotransmitters, regeneration, and maintenance of the required gradientNa+ and K +, conduction of a nerve impulse. Skeletal muscles at rest consume insignificant amounts of ATP, but with physical activity these requirements increase tenfold. In the myocardium, mechanical work is constantly performed, which is necessary for blood circulation. The kidneys use ATP in the process of reabsorbing substances during the formation of urine. In the liver, glycogen, fats, proteins and other compounds are synthesized.

5. DIAGNOSTICS OF MITOCHONDRIAL DISEASES

Mitochondrial diseases are difficult to diagnose. This is determined by the absence of a strict relationship between the mutation site and the clinical phenotype. This means that the same mutation can cause different symptoms, and different mutations can form the same clinical phenotype.

Therefore, for the diagnosis of mitochondrial disease, it is importantan integrated approach based on genealogical, clinical, biochemical, morphological (histological), genetic analyzes.

Genealogical analysis

A family history of sudden infant death syndrome, cardiomyopathies, dementia, early stroke, retinopathies, diabetes, developmental delay may indicate the mitochondrial nature of the disease.

Clinical manifestations of mitochondrial diseases

Myopathic syndrome: muscle weakness and atrophy, decreased myotonic tone, muscle pain, exercise intolerance (increased muscle weakness, vomiting and headache).

Central nervous system and sensory organs: lethargy, coma, delayed psychomotor development, dementia, impaired consciousness, ataxia, dystonia, epilepsy, myoclonic seizures, "metabolic stroke", blindness of central origin, retinitis pigmentosa, optic nerve atrophy, nystagmus, cataracts, ophthalmoplegia, ptosis, visual impairment, hypoacusia, dysarthria, sensory disturbances, dry mouth, hypotension, decreased deep tendon reflexes, stroke-like episodes, hemianopsia.

Peripheral nervous system: axonal neuropathy, impaired motor function of the gastrointestinal tract.

The cardiovascular system: cardiomyopathy (usually hypertrophic), arrhythmia, conduction disturbance.

Gastrointestinal tract: frequent dyspeptic symptoms (vomiting, diarrhea), atrophy of intestinal villi, exocrine pancreatic insufficiency.

Liver: progressive liver failure (especially in infants), hepatomegaly.

Kidneys: tubulopathy (similar to De Toni-Debre-Fanconi syndrome: phosphaturia, glucosuria, aminaciduria), nephritis, renal failure.

Endocrine system: growth retardation, impaired sexual development, hypoglycemia, diabetes mellitus and diabetes insipidus, hypothyroidism, hypoparathyroidism, hypothalamic-pituitary insufficiency, hyperaldosteronism.

Hematopoietic system: pancytopenia, macrocytic anemia.

The main biochemical manifestations of mitochondrial diseases

Level up:

· lactate and pyruvate in the blood (cerebrospinal fluid);

· 3-hydroxybutyric and acetoacetic acids in the blood;

· ammonia in the blood;

· Amino acids;

· fatty acids with different chain lengths;

Myoglobin;

· lipid peroxidation products;

· urinary excretion of organic acids.

Decrease:

· the activity of some enzymes of energy metabolism in mitochondria;

· the content of total carnitine in the blood.

Lactic acidosisis an almost constant companion of mitochondrial diseases, but it also manifests itself in other forms of pathology. Therefore, it is more effective to measure the level of lactate in the venous blood after moderate exercise on a bicycle ergometer.

The main changes in the structure of skeletal muscle in mitochondrial insufficiency

Morphological examination allows using light and electron microscopy in combination with histochemical methods to reveal violations in the number and structure of mitochondria, signs of their dysfunction and a decrease in the activity of mitochondrial enzymes.

Clight microscopy using various types of special staining, including for determining the activity of mitochondrial enzymes, it reveals:

· the phenomenon of "torn" (rough) red fibers (RRF - "ragged" red fibers ) in an amount of more than 5% (when stained according to Gomori, Altman resembles a rupture of fibers along the periphery and is caused by the accumulation of proliferating genetically altered mitochondria under the sarcolemma);

· histochemical signs of mitochondrial enzyme deficiency (Krebs cycle, respiratory chain), especially citrate synthetase, succinate dehydrogenase and cytochrome C oxidase;

· subsarcolemmal accumulation of glycogen, lipids, calcium(it is believed that the accumulation of fatty drops in various tissues, including muscle fibers, occurs as a result of a violation of the oxidation of fatty acids in mitochondria) .

At e microscopy determine:

· proliferation of mitochondria;

· accumulations of abnormal mitochondria under the sarcolemma;

· mitochondrial polymorphism with a violation of the shape and size, disorganization of the cristae;

· the presence of paracrystalline inclusions in mitochondria;

· the presence of mitochondrial-lipid complexes.

Genetic analysis to confirm the diagnosis of mitochondrial disease

Detection of any kind of mitochondrial mutation with a sufficiently high ratio of abnormal to normal mtDNA confirms the diagnosis of mitochondrial disease or syndrome. The absence of a mitochondrial mutation suggests that the patient has a pathology associated with the mutation of nDNA.

It is known that the level of heteroplasmy largely determines the phenotypic manifestation of the mutation. Therefore, when carrying out molecular analysis, it is necessary to estimate the amount of mutant mtDNA. Assessment of the level of heteroplasmy includes detection of the mutation, however, methods for detecting a mutation do not always take into account the level of its heteroplasmy.

1. Cloning method gives reliable quantitative results (the most laborious and time consuming).

2. Fluorescent PCR provides more accurate results with less laboriousness (does not allow detecting small deletions and insertions).

3. Denaturing high-resolution liquid chromatography gives reproducible results for any types of mutations (deletions, insertions, point mutations) in a state of heteroplasmy (the assessment of the level of heteroplasmy is more accurate compared to the previous 2).

4. Real time PCR used to detect andquantifying mtDNA mutations. Use: hydrolysable probes (TaqMan), intercalating dyeSYBR.

The most accurate estimates are given by 3 methods:

· minisequencing ( SNaP - shot ) - determination of single nucleotide substitutions, deletions and insertions with short probes (15–30 nucleotides). A piece of DNA carrying a mutation, for exampleCTstands out and is approved with using PCR. This area is a matrix. The probe has an identical structure, weight 5485 Da, but shorter than the template by one nucleotide. Nucleotides T and C are added to the mixture of the probe and the template. If nucleotide C is attached to the probe, then the "wild" type template and its mass will be 5758 Da. If the nucleotide T - the template was of the mutant type with a mass of 6102 Da. Then the mass of the obtained samples is determined using a mass spectrometer.

· Pyrosequencing - combination of sequencing and synthesis. The matrix is ​​incubated in a mixture of 4 enzymes, 4 deoxynucleotide triphosphates (dATP, dSTP, dGTP, dTTP) and 4 transcription terminatorsdNTP... The addition of a complementary nucleotide is accompanied by a fluorescent biochemical reaction.

· Biplex Invader - allows you to detect 2 mutations at once.

However, with comparable accuracyBiplexInvaderturned out to be the easiest to use, andSNaPshot- the most expensive.

Currently preferred chip technologies , allowing to analyze the main pathogenic mutations of mtDNA in a multitude of samples at once, while establishing the level of heteroplasmy of each individual mutation.

Algorithm for the diagnosis of mitochondrial diseases (by, 2007)

1. Evidence-based clinical suspicion of mitochondrial disease is required. In typical cases, this may be the identification of a clinical picture characteristic of one or another form of mitochondrial encephalomyopathy (MELAS, MERRF, etc.), but the "classic" variants of these phenotypes are relatively rare.

The identification of generally accepted laboratory markers of mitochondrial dysfunction, multisystem, multiple organ damage (this requires a targeted search), as well as the maternal type of inheritance indicate the mitochondrial nature of the disease.

2. MtDNA research in lymphocytes(in patients with clear phenotypes MELAS, MERRF, Leber optic atrophy). When the desired mutation is identified, the diagnosis of a particular mitochondrial disease can be considered confirmed.

3. In the absence of detectable mutations in lymphocytes, a biopsy of the skeletal muscle (usually four-headed or deltoid), because. skeletal muscle is a more reliable source of mtDNA (the absence of cell division in muscle contributes to the "retention" of mitochondria containing mutant mtDNA). Muscle biopsy specimens are divided into 3 parts: one - for microscopic examination (histology, histochemistry and electron microscopy), the second - for enzymological and immunological analysis (study of the characteristics of the components respiratory chain), the third - for molecular genetic analysis.

4. In the absence of known mtDNA mutations in muscle tissue carry out a detailed molecular genetic analysis - sequencing of the entire mtDNA chain (or candidate nuclear DNA genes) in order to identify a new variant of mutation.

5. Identification of a specific biochemical defect in one or another link of the mitochondrial respiratory chain is an alternative to the study of skeletal muscles.

6. TREATMENT OF MITOCHONDRIAL DISEASES

At present, mitochondrial diseases are practically incurable. However, it is possible to either delay the development of the disease or avoid inheriting the pathogenic mitochondrial mutation.

Principles of Mitochondrial Disease Therapy

1. Symptomatic treatment:

The diet is made up depending on the pathogenesis.

· In case of pathology of transport and oxidation of fatty acids, frequent and fractional meals with a decrease in the caloric content of food are recommended.

· If the metabolism of pyruvic acid is disturbed, a ketogenic diet is used to compensate for the deficiency of acetyl-Co-A.

· With a deficiency of CTX enzymes, frequent feeding is used.

· With a deficiency of the respiratory chain and oxidative phosphorylation, the amount of carbohydrates is reduced.

Drug therapy.

· Drugs that activate the transfer of electrons in the respiratory chain (coenzymeQ10 , vitamins K1 and K3, succinic acid preparations, cytochrome C).

· Cofactors of enzymatic reactions of energy metabolism (nicotinamide, riboflavin, carnitine, lipoic acid and thiamine).

· Drugs that reduce the degree of lactic acidosis (dichloroacetate, dimephosphon).

· Antioxidants (ubiquinone, vitamin C and E).

Exclusion of drugs that inhibit energy metabolism (barbiturates, chloramphenicol).

Mechanical ventilation, anticonvulsants, pancreatic enzymes, transfusion of blood components.

Mitochondrial pathology and problems of the pathogenesis of mental disorders

V.S. Sukhorukov

The mitochondrial pathology and problems of pathophysiology of mental disorders

V.S. Sukhorukov
Moscow Research Institute of Pediatrics and Pediatric Surgery of Rosmedtechnologies

Over the past decades, a new direction has been actively developing in medicine, associated with the study of the role of cellular energy metabolism disorders - processes affecting universal cellular organelles - mitochondria. In this regard, the concept of "mitochondrial diseases" appeared.

Mitochondria perform many functions, but their main task is the formation of ATP molecules in the biochemical cycles of cellular respiration. The main processes occurring in mitochondria are the tricarboxylic acid cycle, fatty acid oxidation, carnitine cycle, transport of electrons in the respiratory chain (using I-IV enzyme complexes) and oxidative phosphorylation (V enzyme complex). Mitochondrial dysfunctions are among the most important (often early) stages of cell damage. These disorders lead to insufficient energy supply to cells, disruption of many other important metabolic processes, further development of cellular damage up to cell death. For the clinician, the assessment of the degree of mitochondrial dysfunction is essential both for the formation of ideas about the nature and extent of the processes occurring at the tissue level, and for the development of a plan for the therapeutic correction of the pathological condition.

The concept of "mitochondrial diseases" was formed in medicine at the end of the 20th century due to the recently discovered hereditary diseases, the main etiopathogenetic factors of which are mutations of genes responsible for the synthesis of mitochondrial proteins. First of all, diseases associated with mutations of mitochondrial DNA discovered in the early 60s were studied. This DNA, which has a relatively simple structure and resembles the ring chromosome of bacteria, has been studied in detail. The complete primary structure of human mitochondrial DNA (mitDNA) was published in 1981), and already in the late 1980s, the leading role of its mutations in the development of a number of hereditary diseases was proved. The latter include hereditary atrophy of Leber optic nerves, NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), MERRF syndrome (myoclonus epilepsy with "torn" red fibers in skeletal muscles), MELAS syndrome (mitochondrial encephalomyopathy, lodactate-adenopathy) Kearns-Sayre syndrome (retinitis pigmentosa, external ophthalmoplegia, heart block, ptosis, cerebellar syndrome), Pearson's syndrome (bone marrow damage, pancreatic and hepatic dysfunction), etc. The number of descriptions of such diseases is increasing every year. According to the latest data, the cumulative incidence of hereditary diseases associated with mitDNA mutations reaches 1: 5000 people in the general population.

To a lesser extent, hereditary mitochondrial defects associated with damage to the nuclear genome have been studied. To date, relatively few of them are known (various forms of infant myopathies, diseases of Alpers, Leigh, Barth, Menkes, carnitine deficiency syndromes, some enzymes of the Krebs cycle and the mitochondrial respiratory chain). It can be assumed that their number should be much larger, since the genes encoding information in 98% of mitochondrial proteins are located in the nucleus.

In general, we can say that the study of diseases caused by hereditary disorders of mitochondrial functions has made a kind of revolution in modern concepts of the medical aspects of human energy metabolism. In addition to the contribution to theoretical pathology and medical systematics, one of the main achievements of medical "mitochondriology" was the creation of effective diagnostic tools (clinical, biochemical, morphological and molecular genetic criteria for polysystemic mitochondrial insufficiency), which made it possible to assess polysystemic disorders of cellular energy exchange.

As for psychiatry, already in the 30s of the twentieth century, data were obtained that patients with schizophrenia after physical exertion sharply increase the level of lactic acid. Later, in the form of a formalized scientific hypothesis, the postulate appeared that some mechanisms regulating energy exchange are responsible for the absence of "psychic energy" in this disease. However, for quite a long time such assumptions were perceived as, to put it mildly, "unpromising from a scientific point of view." In 1965 S. Kety wrote: "It is difficult to imagine that a generalized defect in energy metabolism - a process that is fundamental for every cell in the body - could be responsible for highly specialized features of schizophrenia." Nevertheless, the situation changed over the next 40 years. The successes of "mitochondrial medicine" were so convincing that they began to attract the attention of a wider circle of doctors, including psychiatrists. The result of a consistent increase in the number of relevant studies was summed up in the work of A. Gardner and R. Boles "Does" Mitochondrial Psychiatry "Have a Future?" ... The interrogative form of the postulate in the title carried a tinge of exaggerated modesty. The amount of information given in the article was so large, and the authors' logic was so flawless that there was no longer any reason to doubt the promise of “mitochondrial psychiatry”.

To date, there are several groups of evidence for the participation of disturbances in energy processes in the pathogenesis of mental illness. Each of the groups of evidence is discussed below.

Mental Disorders in Mitochondrial Diseases

Differences in the threshold tissue sensitivity to the deficiency of ATP production leaves a significant imprint on the clinical picture of mitochondrial diseases. In this respect, the nervous tissue is primarily of interest as the most energy-dependent. From 40 to 60% of the ATP energy in neurons is spent on maintaining the ion gradient on their outer shell and transferring the nerve impulse. Therefore, dysfunctions of the central nervous system in classic "mitochondrial diseases" are of paramount importance and give reason to call the main symptom complex "mitochondrial encephalomyopathies". Clinically, the focus was on such brain disorders as mental retardation, seizures, and stroke-like episodes. The severity of these forms of pathology in combination with severe somatic disorders can be so great that other, milder disorders associated, in particular, with personal or emotional changes, remain in the shadows.

The accumulation of information about mental disorders in mitochondrial diseases began to occur in comparison with the above disorders much later. Nevertheless, there is now sufficient evidence of their existence. Depressive and bipolar affective disorders, hallucinations, and personality changes have been described in Kearns-Sayre syndrome, MELAS syndrome, chronic progressive external ophthalmoplegia, and Leber's hereditary optic neuropathy.

Quite often, the development of classic signs of mitochondrial disease is preceded by moderate mental disorders. Therefore, patients can initially be seen by psychiatrists. In these cases, other symptoms of mitochondrial disease (photophobia, vertigo, fatigue, muscle weakness, etc.) are sometimes regarded as psychosomatic disorders. The renowned researcher of mitochondrial pathology P. Chinnery in an article written jointly with D. Turnbull points out: “Psychiatric complications are constantly associated with mitochondrial disease. They usually take the form of reactive depression ... We have repeatedly observed cases of severe depression and suicidal attempts even before (italics of the authors of the article), as the diagnosis was made. "

Difficulties in establishing the true role of mental disorders in the diseases under consideration are also associated with the fact that psychiatric symptoms and syndromes can be regarded in some cases as a reaction to a difficult situation, in others - as a consequence of organic brain damage (in the latter case, the term "psychiatry" in general not used).

Based on the materials of a number of reviews, we present a list of mental disorders described in patients with proven forms of mitochondrial diseases 1. These violations can be divided into three groups. I. Psychotic disorders - hallucinations (auditory and visual), symptoms of schizophrenia and schizophrenic states, delirium. In some cases, these disorders follow progressive cognitive impairment. II. Affective and anxiety disorders - bipolar and unipolar depressive states (they are described most often), panic states, phobias. III. Cognitive impairment in the form of attention deficit hyperactivity disorder. This syndrome has been described not only in patients diagnosed with mitochondrial disease, but also in their relatives. In particular, a case is described when a disease, which was based on the deletion of one nucleotide pair of mitDNA in the region of the transport RNA gene, first manifested itself in a boy in school years in the form of attention deficit hyperactivity disorder. The progression of mitochondrial encephalomyopathy led to the death of this patient at the age of 23 years. IV. Personality disorders. Such disorders have been described in a number of cases with a diagnosis confirmed by molecular genetic studies. Typically, personality disorders develop after cognitive impairment. A case of autism in a patient with a point mutation of mitDNA in the region of the transport RNA gene is described.

Common signs of mitochondrial and mental illness

We are talking about a certain clinical similarity of some mental diseases and mitochondrial syndromes, as well as the general types of their inheritance.

First of all, attention is drawn to the data on the prevalence of cases of maternal inheritance of certain mental diseases, in particular bipolar disorders. Such inheritance cannot be explained from the standpoint of autosomal mechanisms, and the equal number of men and women among patients with bipolar disorders makes it unlikely that X-linked inheritance is possible in this case. The most adequate explanation for this may be the concept of transmission of hereditary information through mitDNA. There is also a tendency towards maternal inheritance in schizophrenic patients. True, in this respect there is an alternative explanation used in our context: it is assumed that this tendency may be due to unequal conditions of patients of different sexes in search of a partner.

An indirect confirmation of the connection between mitochondrial and some mental diseases is also the tendency to the cyclical nature of their clinical manifestations. This is common knowledge for diseases such as bipolar disorder. However, at present, data on ultra-, circadian and seasonal rhythms of clinical manifestations of dysenergetic states are beginning to accumulate in mitochondriology. This feature even determined the name of one of their nosological mitochondrial cytopathies - "cyclic vomiting syndrome".

Finally, the considered similarity of the two groups of diseases appears in their accompanying somatic signs. Psychosomatic symptoms well known to psychiatrists, such as hearing impairment, muscle pain, fatigue, migraines, irritable bowel syndrome, are constantly described in the symptom complex of mitochondrial diseases. As A. Gardner and R. Boles write, “if mitochondrial dysfunction is one of the risk factors for the development of certain psychiatric diseases, these comorbid somatic symptoms may rather be a consequence of mitochondrial dysfunction, rather than a manifestation of“ communicative distress ”,“ hypochondrial pattern ”or“ secondary gain ”. Sometimes such terms are used to refer to the phenomenon of somatization of mental disorders.

In conclusion, let us point out one more similarity: an increase in white matter density determined by magnetic resonance imaging is noted not only in bipolar affective disorders and major depression with a late onset, but also in cases of ischemic changes in mitochondrial encephalopathies.

Signs of mitochondrial dysfunction in mental illness

Schizophrenia

As mentioned above, mentions of signs of lactic acidosis and some other biochemical changes, indicating a violation of energy metabolism in schizophrenia, began to appear in the 30s of the twentieth century. But only starting from the 90s, the number of relevant works began to grow especially noticeably, and the methodological level of laboratory research also increased, which was reflected in a number of review publications.

On the basis of the published works D. Ben-Shachar and D. Laifenfeld divided all the signs of mitochondrial disorders in schizophrenia into three groups: 1) morphological disorders of mitochondria; 2) signs of a violation of the oxidative phosphorylation system; 3) violation of the expression of genes responsible for mitochondrial proteins. This division can be supported by examples from other works.

Autopsy of the brain tissue of patients with schizophrenia L. Kung and R. Roberts revealed a decrease in the number of mitochondria in the frontal cortex, caudate nucleus and shell. At the same time, it was noted that it was less pronounced in patients receiving antipsychotics, in connection with which the authors considered it possible to talk about the normalization of mitochondrial processes in the brain under the influence of neuroleptic therapy. This gives grounds to mention the article by N.S. Kolomeets and N.A. Uranium on mitochondrial hyperplasia in the presynaptic terminals of axons in the substantia nigra in schizophrenia.

L. Cavelier et al. Examining autopsy material from the brain of patients with schizophrenia revealed a decrease in the activity of the IV complex of the respiratory chain in the caudate nucleus.

The results presented made it possible to suggest a primary or secondary role of mitochondrial dysfunction in the pathogenesis of schizophrenia. However, the autopsy material examined belonged to patients treated with antipsychotics, and, naturally, mitochondrial disorders were associated with drug exposure. Note that such assumptions, often not unfounded, accompany the entire history of the detection of mitochondrial changes in various organs and systems in mental and other diseases. As for the possible influence of the neuroleptics themselves, it should be recalled that the tendency to lactic acidosis in patients with schizophrenia was discovered as early as 1932, almost 20 years before their appearance.

A decrease in the activity of various components of the respiratory chain was found in the frontal and temporal cortex, as well as in the basal ganglia of the brain and other tissue elements - platelets and lymphocytes of schizophrenic patients. This made it possible to speak about the polysystemic nature of mitochondrial insufficiency. S. Whatley et al. , in particular, they showed that in the frontal cortex the activity of the IV complex decreases, in the temporal cortex - the I, III and IV complexes; in the basal ganglia - I and III complexes, no changes were found in the cerebellum. It should be noted that in all areas studied, the activity of the intramitochondrial enzyme, citrate synthase, corresponded to the control values, which gave grounds to speak of the specificity of the results obtained for schizophrenia.

In addition to the studies considered, one can cite the carried out in 1999-2000. J. Prince et al. who studied the activity of respiratory complexes in different parts of the brain of schizophrenic patients. These authors did not find signs of changes in the activity of complex I, however, the activity of complex IV was reduced in the caudate nucleus. The latter, as well as the activity of complex II, was increased in the shell and in the nucleus accumbens. Moreover, the increase in the activity of complex IV in the shell significantly correlated with the severity of emotional and cognitive dysfunction, but not with the degree of motor disorders.

It should be noted that the authors of most of the above works explained the signs of energy metabolism disorders by the effect of neuroleptics. In 2002, very interesting data in this regard were published by A. Gardner et al. on mitochondrial enzymes and ATP production in muscle biopsies from schizophrenic patients treated with antipsychotics and not treated with them. They found that a decrease in the activity of mitochondrial enzymes and ATP production was found in 6 out of 8 patients who did not receive antipsychotics, and an increase in ATP production was found in patients on antipsychotic therapy. These data to a certain extent confirmed the conclusions made earlier in the work of L. Kung and R. Roberts.

In 2002, the results of another notable work were published. It studied the activity of complex I of the respiratory chain in platelets of 113 schizophrenic patients in comparison with 37 healthy ones. The patients were divided into three groups: 1st - with an acute psychotic episode, 2nd - with a chronic active form, and 3rd - with residual schizophrenia. The results showed that the activity of complex I was significantly increased in comparison with the control in patients of groups 1 and 2 and decreased in patients in group 3. Moreover, a significant correlation was found between the obtained biochemical parameters and the severity of clinical symptoms of the disease. Similar changes were obtained when studying the RNA and protein of the flavoprotein subunits of complex I in the same material. The results of this study thus not only confirmed the high likelihood of polysystemic mitochondrial failure in schizophrenia, but also allowed the authors to recommend appropriate laboratory methods for monitoring the disease.

After 2 years in 2004, D. Ben-Shachar et al. published interesting data on the effect of dopamine on the respiratory chain of mitochondria, which is assigned a significant role in the pathogenesis of schizophrenia. It was found that dopamine can inhibit the activity of complex I and ATP production. In this case, the activity of complexes IV and V does not change. It turned out that, unlike dopamine, norepinephrine and serotonin do not affect ATP production.

Remarkable is the emphasis made in the above studies on the dysfunction of complex I of the mitochondrial respiratory chain. This kind of change may reflect relatively moderate disturbances in mitochondrial activity, which are more significant from the point of view of functional regulation of energy exchange than gross (close to lethal for the cell) drops in cytochrome oxidase activity.

Let us now briefly dwell on the genetic aspect of mitochondrial pathology in schizophrenia.

In 1995-1997 L. Cavelier et al. it was found that the level of "normal deletion" of mitDNA (the most common deletion of 4977 base pairs, affecting the genes of subunits I, IV and V of the complexes and underlying several severe mitochondrial diseases, such as Kearns-Sayre syndrome, etc.) is not changed in autopsy material of the brain of patients with schizophrenia, does not accumulate with age and does not correlate with altered cytochrome oxidase activity. By sequencing the mitochondrial genome in schizophrenic patients, the researchers of this group showed the presence of different from the control polymorphism of the cytochrome b gene.

In these years, a series of works by R. Marchbanks et al. Was also published. who studied the expression of both nuclear and mitochondrial RNA in the frontal cortex in cases of schizophrenia. They found that all quantitatively increased sequences compared to control were related to mitochondrial genes. In particular, the expression of the mitochondrial gene of the 2nd subunit of cytochrome oxidase was significantly increased. Four other genes were associated with mitochondrial ribosomal RNA.

Japanese researchers, examining 300 cases of schizophrenia, found no signs of the 3243AG mutation (causing a disorder in complex I in MELAS syndrome). No increased mutational frequency was found in the mitochondrial genes of the 2nd subunit of complex I, cytochrome b and mitochondrial ribosomes in schizophrenia in the work of K. Gentry and V. Nimgaonkar.

R. Marchbanks et al. discovered a mutation in 12027 of the mitDNA nucleotide pair (gene of the 4th subunit of complex I), which was present in men with schizophrenia and which was not in women.

The characteristics of the three nuclear genes of complex I were studied in the prefrontal and visual cortex of schizophrenic patients by R. Karry et al. ... They found that transcription and translation of some subunits was decreased in the prefrontal cortex and increased in the visual (the authors interpreted these data in accordance with the concept of "hypofrontality" in schizophrenia). The study of genes (including genes for mitochondrial proteins) in the hippocampal tissue in patients treated with antipsychotics with schizophrenia did not reveal any changes.

Japanese researchers K. Iwamoto et al. Studying changes in the genes responsible for hereditary information for mitochondrial proteins in the prefrontal cortex in schizophrenia in connection with treatment with antipsychotics, obtained evidence in favor of a drug effect on cellular energy metabolism.

The above results can be supplemented by data from intravital studies, which were reviewed by W. Katon et al. : when studying the distribution of the phosphorus isotope 31P using magnetic resonance spectroscopy, a decrease in the level of ATP synthesis in the basal ganglia and temporal lobe of the brain of patients with schizophrenia was revealed.

Depression and bipolar disorder

Japanese researchers T. Kato et al. Magnetic resonance spectroscopy revealed a decrease in intracellular pH and the level of phosphocreatine in the frontal lobe of the brain in patients with bipolar disorders, including those who did not receive treatment. By the same authors, a decrease in the level of phosphocreatine in the temporal lobe was found in patients resistant to lithium therapy. Other authors have found a decrease in ATP levels in the frontal lobe and basal ganglia of patients with major depression. Note that similar symptoms were observed in patients with some mitochondrial diseases.

As for the molecular genetic data, it should be noted right away that the results of a number of studies indicate that there is no evidence of the involvement of mitDNA deletions in the development of mood disorders.

A number of studies of mitDNA polymorphism, in addition to the very fact of difference in its haplotypes in patients with bipolar disorders and subjects from the control group, revealed some mutations characteristic of the former, in particular, in positions 5178 and 10398 - both positions are located in the zone of genes of complex I.

There are reports of the presence of mutations in the genes of complex I, and not only in mitochondrial, but also in nuclear. Thus, in cultures of lymphoblastoid cells obtained from patients with bipolar disorders, a mutation was found in the NDUFV2 gene, localized on chromosome 18 (18p11), and encoding one of the subunits of complex I. Sequencing of mitDNA in patients with bipolar disorders revealed a characteristic mutation in position 3644 of the ND1 subunit gene, also belonging to complex I. An increase in the level of translation (but not transcription) was found for some subunits of complex I in the visual cortex of patients with bipolar disorders. Among other studies, we cite two works in which the genes of the respiratory chain were investigated and their molecular genetic abnormalities were found in the prefrontal cortex and hippocampus of patients with bipolar disorders. In one of the works of A. Gardner et al. in patients with major depression, a number of mitochondrial enzyme disorders and a decrease in the level of ATP production in musculoskeletal tissue were revealed, while a significant correlation was found between the degree of decrease in ATP production and clinical manifestations of mental disorder.

Other mental disorders

There is little research into mitochondrial dysfunction in other mental disorders. Some of them were mentioned in the previous sections of the review. Here we specially mention the work of P. Filipek et al. , in which 2 children with autism and a mutation on chromosome 15, in the 15q11-q13 region, were described. Both children showed moderate motor developmental delay, lethargy, severe hypotension, lactic acidosis, decreased activity of complex III, and mitochondrial hyperproliferation in muscle fibers. This work is notable for the fact that it was the first to describe mitochondrial disorders in the symptom complex of a disease etiologically associated with a specific region of the genome.

Genealogical data on the possible role of mitochondrial disorders in the pathogenesis of mental illness

Above, we have already mentioned such a feature of a number of mental diseases as an increased frequency of cases of maternal inheritance, which may indirectly indicate the participation of mitochondrial pathology in their pathogenesis. However, there is also more convincing evidence of the latter in the literature.

In 2000, the data obtained by F. McMahon et al. Were published. who sequenced the entire mitochondrial genome in 9 unrelated probands, each of whom came from a large family with maternal transmission of bipolar disorders. There were no obvious differences in haplotypes compared to control families. However, for some positions of mitDNA (709, 1888, 10398, and 10463), a disproportion between sick and healthy was found. At the same time, one can note the coincidence of the data on position 10398 with the already mentioned data of the Japanese authors, who suggested that the 10398A polymorphism of mitDNA is a risk factor for the development of bipolar disorders.

The most significant genealogical evidence of the role of mitochondrial dysfunctions in the development of mental disorders is the fact that patients with classical mitochondrial diseases have relatives (more often on the maternal side) with moderate mental disorders. Anxiety and depression are frequently mentioned among these disorders. So, in the work of J. Shoffner et al. it was found that the severity of depression in mothers of "mitochondrial" patients is 3 times higher than in the control group.

Noteworthy is the work of B. Burnet et al. , who for 12 months conducted anonymous survey of patients with mitochondrial diseases, as well as their family members. Among the questions were those related to the health status of the parents and close relatives of patients (on the paternal and maternal side). Thus, 55 families (group 1) with a putative maternal and 111 families (group 2) with a putative non-maternal mode of mitochondrial disease inheritance were studied. As a result, relatives of patients on the maternal side, in comparison with the paternal side, were found to have a higher frequency of several pathological conditions. Among them, along with migraines and irritable bowel syndrome, there was depression. In group 1, intestinal dysfunction, migraine and depression were observed in a greater percentage of mothers from the surveyed families - 60, 54 and 51%, respectively; in group 2 - in 16, 26 and 12%, respectively (p<0,0001 для всех трех симптомов). У отцов из обеих групп это число составляло примерно 9-16%. Достоверное преобладание указанных признаков имело место и у других родственников по материнской линии. Этот факт является существенным подтверждением гипотезы о возможной связи депрессии с неменделевским наследованием, в частности с дисфункцией митохондрий.

Pharmacological aspects of mitochondrial pathology in mental illness

The effect of drugs used in psychiatry on mitochondrial function

In the previous sections of the review, we have already briefly touched upon the issues of therapy. In particular, the question of the possible effect of antipsychotics on mitochondrial functions was discussed. It was found that chlorpromazine and other phenothiazine derivatives, as well as tricyclic antidepressants, can affect energy metabolism in the brain tissue: they can reduce the level of oxidative phosphorylation in certain parts of the brain, are able to uncouple oxidation and phosphorylation, reduce the activity of complex I and ATPase, and reduce the level of utilization ATP. However, the interpretation of the facts in this area requires great care. Thus, the uncoupling of oxidation and phosphorylation under the influence of neuroleptics was noted by no means in all areas of the brain (it is not determined in the cortex, thalamus and caudate nucleus). In addition, there are experimental data on the stimulation of mitochondrial respiration by antipsychotics. In the previous sections of the review, we also cite works showing the positive effect of antipsychotics on mitochondrial function.

Carbamazepine and valproate are known for their ability to suppress mitochondrial function. Carbamazepine leads to an increase in the level of lactate in the brain, and valproate is able to inhibit the processes of oxidative phosphorylation. The same kind of effects (albeit only in high doses) were revealed in an experimental study of serotonin reuptake inhibitors.

Lithium, which is widely used in the treatment of bipolar disorders, also appears to have a positive effect on cellular energy metabolism. It competes with sodium ions by participating in the regulation of calcium pumps in mitochondria. A. Gardner and R. Boles in their review cite the words of T. Gunter, a well-known specialist in the metabolism of calcium in mitochondria, who believes that lithium "can affect the rate at which this system adapts to different conditions and different needs for ATP." In addition, lithium is believed to decrease the activation of the apoptotic cascade.

A. Gardner and R. Boles cite in the mentioned review a lot of indirect clinical evidence of a positive effect of psychotropic drugs on symptoms, presumably dependent on dysenergetic processes. Thus, intravenous administration of chlorpromazine and other antipsychotics reduces migraine headaches. The efficacy of tricyclic antidepressants in the treatment of migraine, cyclic vomiting syndrome and irritable bowel syndrome is well known. Carbamazepine and valproate are used in the treatment of neuralgias and other pain syndromes, including migraines. Lithium and serotonin reuptake inhibitors are also effective in treating migraines.

Analyzing the above rather contradictory information, we can conclude that psychotropic drugs are undoubtedly capable of influencing the processes of energy exchange in the brain and mitochondrial activity. Moreover, this influence is not unambiguously stimulating or inhibiting, but rather “regulating”. At the same time, it can be different in the neurons of different parts of the brain.

The foregoing suggests that the lack of energy in the brain, perhaps, concerns primarily the areas especially affected by the pathological process.

The effectiveness of energotropic drugs for mental disorders

In the aspect of the problem under consideration, it is important to obtain evidence of a decrease or disappearance of the psychopathological components of mitochondrial syndromes.

In this aspect, the report of T. Suzuki et al. about a patient with schizophrenia-like disorders on the background of MELAS syndrome. After the application of coenzyme Q10 and nicotinic acid, the patient's mutism disappeared for several days. There is also a study that provides evidence of the successful use of dichloroacetate (often used in "mitochondrial medicine" to lower lactate levels) in a 19-year-old man with MELAS for its effects on delirium with auditory and visual hallucinations.

The literature also contains a description of the history of a patient with MELAS syndrome with identified point mutation 3243 in mitDNA. This patient developed psychosis with auditory hallucinations and persecutory delusions, which was controlled within a week with low doses of haloperidol. Later, however, he developed mutism and affective dullness, which did not respond to treatment with haloperidol, but disappeared after treatment for a month with idebenone (a synthetic analogue of coenzyme Q10) at a dose of 160 mg / day. In another patient with MELAS syndrome, coenzyme Q10 at a dose of 70 mg / day helped to cope with persecution mania and aggressive behavior. The success of the use of coenzyme Q10 in the treatment of MELAS syndrome was also stated in the work: we are talking about a patient who not only prevented stroke-like episodes, but also relieved headaches, tinnitus and psychotic episodes.

There are also reports on the effectiveness of energotropic therapy in patients with mental illness. Thus, a 23-year-old patient with a therapeutically resistant depression was described, the severity of which significantly decreased after 2-month use of coenzyme Q10 at a dose of 90 mg per day. A similar case is described in the work. The use of carnitine in combination with energy metabolism cofactors has been shown to be effective in the treatment of autism.

Thus, in the modern literature there is some evidence of a significant role of mitochondrial disorders in the pathogenesis of mental disorders. Note that in this review we did not dwell on neurodegenerative diseases of the elderly, for most of which the importance of mitochondrial disorders has already been proven, and their consideration requires a separate publication.

Based on the data presented, it can be argued that there is a need to unite the efforts of psychiatrists and specialists dealing with mitochondrial diseases, aimed both at studying the dysenergetic foundations of disorders of higher nervous activity and analyzing the psychopathological manifestations of diseases associated with disorders of cellular energy exchange. In this aspect, both new diagnostic (clinical and laboratory) approaches and the development of new methods of treatment require attention.

1 It should be noted that among the relevant descriptions, cases with the identified mitDNA mutation 3243AG, a generally recognized cause of the development of MELAS syndrome, occupy a large place.

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Doctors began to observe how mitochondrial disease manifested itself as early as the 20th century. In an effort to determine what any of the mitochondrial diseases could be from, experts have discovered more than 50 types of diseases that have a connection with disorders affecting mitochondria.

Depending on the causes, there are three main subgroups of mitochondrial diseases, namely:

• Diseases caused by mutations in mitochondrial DNA. Such defects are associated with a point mutation of various elements and are inherited mainly from the mother. Also, structural dislocation can cause disease. This category of diseases includes such hereditary syndromes of Kearns-Sayre, Pearson, Leber, etc.
• Diseases caused by defects at the level of nuclear DNA. Mutations impair the functioning of mitochondria. In addition, they can cause negative changes in enzymes involved in the cyclic biochemical process, in particular, in the provision of cells in the body with oxygen. These include the Syndromes of Luft and Alpers, diabetic diseases, etc.
• Diseases caused by defects at the level of nuclear DNA and, as a consequence, causing secondary deformation of mitochondrial DNA. The list of secondary changes includes liver failure and syndromes, such as that identified by De Toni-Debre-Fanconi.

Symptoms

Over a long period of time, mutations and, as a result, mitochondrial diseases may not appear in a minor patient. However, over time, the accumulation of unhealthy organelles increases, as a result, the first signs of a disease begin to appear.

Since diseases of the mitchondrial group represent a whole group of pathologies, the signs of these diseases differ significantly depending on which organs and systems of the child's body were damaged. Given the relationship between mitochondrial defects and energy function, it is possible to determine a particular susceptibility to damage to the nervous and muscular systems.

Among the characteristic signs of the pathology of the muscular system, one can recognize:

• Restriction or complete absence of motor activity due to the inability to perform normal activities due to muscle weakness or, as this condition is called, myopathy.
• Low blood pressure.
• Pain syndrome or muscle cramps accompanied by severe pain.

In children, first of all, headache, intense and repeated vomiting, and weakness after minimal physical exertion are manifested.

If we are talking about damage to the nervous system, then the following manifestations take place:

• lag in psychomotor development;
• inability to perform actions that the child coped with earlier - developmental regression;
• seizures;
• periodic manifestations of apnea and tachypnea;
• frequent loss of consciousness and falling into a coma;
• changes in the level of acid-base balance;
• change in gait.

In older children, you may notice numbness, paralysis, loss of sensitivity, stroke-like seizures, pathologies in the form of involuntary movements, etc.

Touching the sensory organs is expressed in deterioration of visual function, ptosis, cataracts, defects of the retina and visual field, hearing impairment or complete deafness of a neurosensory nature. Organ damage in the child's body manifests itself in the form of problems with the heart, liver, kidneys, and pancreas. As for diseases associated with the endocrine system, it is noted here:

• lag in growth and sexual development,
• decreased production of glucose by the body,
• dysfunction of the thyroid gland,
• other metabolic problems.

Diagnosis of mitochondrial diseases in a child

In order to diagnose the presence of mitochondrial diseases, the doctor examines the history, conducts a physical examination, examining primarily the strength of the child and his endurance. Additionally, an examination by a neuropathologist is prescribed, including an assessment of vision, reflexes, speech and cognitive abilities. With the help of specialized tests - muscle biopsy, MRI, and so on - the suspicions are confirmed. Also, computed and magnetic resonance imaging and DNA diagnostics are performed with consultation with geneticists.

Complications

What are dangerous mitochondrial defects depends on the type of disease. For example, if the muscular system is damaged, there is complete paralysis and disability, including intellectual regression.

Treatment

What can you do

First aid from parents depends on what exactly the manifestations of the disease are. In any case, if you have the slightest suspicion and deviations from the norm, you need to contact a specialist and find out what to do with the disease, if any.

What the doctor does

Regardless of the type of disease, it can be treated by introducing drugs that normalize energy metabolism. Also, the child is prescribed symptomatic and specialized treatment in the manner prescribed for a specific disease. Exercise and physiotherapy procedures help to cure pathologies faster or normalize the patient's condition.

Prophylaxis

Mitochondrial diseases cannot be prevented because they occur at the genetic level. The only way to minimize the risks somewhat is to lead a healthy lifestyle without bad habits.

Description:

Mitochondrial diseases are a group of hereditary diseases associated with defects in the functioning of mitochondria, leading to impaired energy functions in eukaryotic cells, in particular, in humans.
Mitochondrial diseases are caused by genetic, structural, biochemical defects of mitochondria, leading to disorders of tissue respiration. They are transmitted only through the female line to children of both sexes, since sperm cells transmit half of the nuclear genome to the zygote, and the egg cell supplies both the second half of the genome and mitochondria. Pathological disorders of cellular energy metabolism can manifest themselves in the form of defects in various links in the Krebs cycle, in the respiratory chain, beta-oxidation processes, etc.

Not all enzymes and other regulators required for efficient mitochondrial function are encoded by mitochondrial DNA. Most of the mitochondrial functions are controlled by the nuclear.

Two groups of mitochondrial diseases can be distinguished:

Pronounced hereditary syndromes caused by mutations of genes responsible for mitochondrial proteins (Barth syndrome, Kearns-Sayre syndrome, Pearson syndrome, MELAS syndrome, MERRF syndrome, and others).

Secondary mitochondrial diseases, including impaired cellular energy exchange as an important link in the formation of pathogenesis (connective tissue diseases, glycogenosis, liver failure, pancytopenia, as well as diabetes, and others).

Causes of mitochondrial diseases:

Mitochondrial damage is mainly caused by & nbsp & nbsp exposure to reactive oxygen species (ROS). Currently, it is believed that most ROS are formed by complexes I and III, probably due to the release of electrons under the influence of NAD-H and FAD-N in CPE. Mitochondria use approximately 85% of the oxygen consumed by the cell in the formation of ATP. & Nbsp & nbsp During the normal process, & nbsp & nbsp OF from 0.4% to 4.0% of all oxygen consumed in the mitochondria is converted into superoxide radicals (O2-). Superoxide is transformed to hydrogen peroxide (H2O2) with the help of detoxification enzymes - & nbsp & nbsp manganese superoxide dismutase (Mn-SOD) or zinc / copper superoxide dismutase (Cu / Zn SOD) - and then to water using glutathione peroxidase (GP III) or peroxide III). However, if these enzymes are not able to quickly & nbsp & nbsp convert ROS such as superoxide radicals to water, oxidative damage occurs and accumulates in mitochondria. & Nbsp & nbsp Glutathione in PR is one of the main antioxidants in the body. Glutathione is a tripeptide containing glutamine, glycine and cysteine. GP requires selenium as a cofactor.

It has been shown that in vitro superoxide damages the iron-sulfur cluster located in the active center of aconitase, the fertent of the TCC cycle. Because of this, iron reacts with H2O2 to form hydroxyl radicals via the Fenton reaction. In addition, nitric oxide (NO) is produced in mitochondria by mitochondrial nitric oxide synthase (MtCOA), and also freely diffuses into mitochondria from the cytosol. NO reacts with O2 to form another radical, peroxynitrite (ONOO-). Together, these two radicals and other radicals can cause significant damage to mitochondria and other cell components.

In mitochondria, elements that are particularly susceptible to free radicals are lipids, proteins, redox enzymes, and mtDNA. Direct damage to mitochondrial proteins reduces their affinity for substrates or coenzymes and thus impairs their function. The problem is compounded by the fact that if mitochondrial damage occurs, mitochondrial function can be compromised by the increased requirements of the cell for energy repair processes. Mitochondrial dysfunction can lead to a chain process in which mitochondrial damage entails additional damage.

Complex I is especially sensitive to the effects of nitric oxide (NO). In animals that were injected with natural and synthetic antagonists of complex I, as a rule, neuronal death is observed. Complex I dysfunction has been associated with Leber's hereditary optic neuropathy, Parkinson's disease, and other neurodegenerative conditions.
induces the formation of superoxide in mitochondria by endothelial cells, which is an important mediator of diabetic complications such as cardiovascular diseases. The formation of superoxide in the endothelium also contributes to the development, hypertension, aging, ischemia-reperfusion injuries, etc.

Inflammatory mediators such as tumor factor α (TNFα) in vitro have been associated with mitochondrial dysfunction & nbsp & nbsp and increased KGF production. In a model of congestive heart failure, the addition of TNFα to the culture of cardiomyocytes increased the formation of ROS and myocyte hypertrophy. TNFα causes mitochondrial dysfunction & nbsp & nbsp by restoring the activity of complex III in CPE, increasing the formation of ROS and damage to mtDNA.

Nutrient deficiency or excess can also lead to mitochondrial dysfunction. Vitamins, minerals, and other metabolites work as necessary cofactors for the synthesis and functioning of mitochondrial enzymes and other constituents that support mitochondrial function, and a diet lacking in micronutrients can accelerate mitochondrial aging and promote neurodegeneration. For example, enzymes involved in the heme synthesis chain require sufficient amounts of pyridoxine, iron, copper, zinc, and riboflavin. Lack of nutrients required for any of the components of the TCC or CPE cycle can lead to an increase in the production of free radicals and damage to mtDNA.

It is well known that nutritional deficiencies are a widespread cause of the pathogenesis of many diseases and are a major controversy in public health. & Nbsp & nbsp Iron deficiency is a major mediator in a common burden of disease affecting approximately 2 billion people, mainly women and children. This is the most common type of nutritional deficiency. Low iron status reduces mitochondrial activity & nbsp & nbsp by turning off complex IV and increasing oxidative stress. The mechanisms underlying the process of the influence of nutrient deficiency (and in some cases excess, as with iron overload) on the occurrence, development and progression of diseases resulting from impaired mitochondrial functions have already been studied.

Inheritance of mitochondrial diseases:

Mitochondria are inherited differently from nuclear genes. Nuclear genes in each somatic cell are usually represented by two alleles (with the exception of most sex-linked genes in the heterogametic sex). One allele is inherited from the father, the other from the mother. However, mitochondria contain their own DNA, and each human mitochondria usually contains from 5 to 10 copies of a circular DNA molecule (see Heteroplasmy), and all mitochondria are inherited from the mother. When a mitochondrion divides, copies of DNA are randomly distributed among its offspring. If only one of the original DNA molecules contains a mutation, as a result of random distribution, such mutant molecules can accumulate in some mitochondria. Mitochondrial disease begins to manifest itself at the moment when a noticeable number of mitochondria in many cells of a given tissue acquire mutant DNA copies (threshold expression).

Mutations in mitochondrial DNA occur, for various reasons, much more often than in nuclear. This means that mitochondrial diseases often manifest themselves due to spontaneous re-emerging mutations. Sometimes the rate of mutation increases due to mutations in nuclear genes that code for enzymes that control mitochondrial DNA replication.

Mitochondrial Disease Symptoms:

The effects of mitochondrial disease are very diverse. Due to the different distribution of defective mitochondria in different organs, a mutation in one person can lead to liver disease, and in another to brain disease. The magnitude of the manifestation of a defect can be large or small, and it can change significantly, slowly increasing over time. Some minor defects only lead to the inability of the patient to withstand physical activity appropriate for his age, and are not accompanied by serious painful manifestations. Other defects can be more dangerous, leading to serious pathology.

In general, mitochondrial diseases are more pronounced when defective mitochondria are localized in muscles, brain, and nervous tissue, since these organs require the most energy to perform their respective functions.

Despite the fact that the course of mitochondrial diseases varies greatly from patient to patient, several main classes of these diseases have been distinguished based on common symptoms and specific mutations that cause the disease.

In addition to the relatively common mitochondrial, there are:

7. Mitochondrial neurogastrointenstinal: gastrointestinal pseudo-obstruction and cachexia, neuropathy, encephalopathy with changes in the white matter of the brain.

Treatment for mitochondrial diseases:

For treatment are prescribed:

Currently, treatment of mitochondrial diseases is under development, but symptomatic prevention with vitamins is a common therapeutic method. In particular, coenzyme Q, which is used as a cytoprotector and antioxidant in cardiomyopathies, and riboflavin and nicotinamide, have been effective in the treatment of MELAS syndrome in a number of patients. Pyruvates are also used as one of the methods.

Currently, experimental work is underway to study the possibility of in vitro fertilization using a chimeric egg, the nucleus of which is obtained from the egg of a patient with mitochondrial disease, and the cytoplasm from another egg from a woman with normally functioning mitochondria (nucleus replacement).

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 a high level of basal metabolism. It was hypothesized that these changes are associated with impaired oxidative phosphorylation processes in the mitochondria of muscle tissue. 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 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 erythrocytes) and producing ATP. Mitochondria are 1.5 μm long and 0.5 μm wide. Their renewal occurs continuously throughout the entire cell cycle. Organella has 2 membranes - external and internal. From the inner 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 circular DNA molecule, specific RNA, granules of calcium and magnesium salts. Enzymes involved in oxidative phosphorylation (complex of cytochromes b, c, a and a3) and electron transfer are fixed on the inner membrane. It is an energy-transforming membrane that converts the chemical energy of oxidation of substrates into energy, which is accumulated in the form of ATP, creatine phosphate, etc. Enzymes involved in the 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 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. Reduced coenzymes NADH and FADH are oxidized in the respiratory chain, which is represented by 5 respiratory complexes.

In the process of electron transfer, energy is accumulated in the form of ATP, creatine phosphate and other high-energy 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, only mtDNA is encoded);
• 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 the synthesis of ATP).

In addition, the electrons of the 4 beta-oxidized fatty acids are carried by the electron transfer protein.

Another important process is carried out in mitochondria - beta-oxidation of fatty acids, as a result of which acetyl-CoA and carnitine esters are formed. In each cycle of fatty acid oxidation, 4 enzymatic reactions take place.

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

In 1963, it was found that mitochondria have their own unique genome, inherited through the maternal line. It is represented by a single small circular 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 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 differs from the nuclear genome. First, it does not contain introns, which provides a high gene density compared to nuclear DNA. Second, most mRNAs do not contain 5 "-3" untranslated sequences. Third, mtDNA has a D-loop, which is its regulatory region. Replication is a two-step process. The differences between the genetic code of mtDNA and the nuclear one were also revealed. Of particular note is that there are a large number of copies of the former. Each mitochondrion contains 2 to 10 copies or more. Considering the fact that cells can contain hundreds and thousands of mitochondria, up to 10 thousand copies of mtDNA are possible. It is highly susceptible 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 major rearrangements of mtDNA (p-mutations).

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