Examples without mitochondrial protists and causes of loss. Mitochondrial diseases
The important features of the mitochondrial type of pathology inheritance are:- the presence of pathology in all children of a sick mother; – the birth of healthy children from a sick father and a healthy mother. These features are explained by the fact that mitochondria are inherited only from the mother. The proportion of the paternal mitochondrial genome in the zygote is DNA from 0 to 4 mitochondria, and the maternal genome is DNA from about 2500 mitochondria. In addition, after fertilization, paternal DNA replication is blocked.
The mitochondrial genome has now been sequenced. It contains 16,569 base pairs and encodes two ribosomal RNAs (12S and 16S), 22 transfer RNAs, and 13 polypeptides. – subunits of enzymatic complexes of oxidative phosphorylation. The other 66 subunits of the respiratory chain are encoded in the nucleus.
Examples of diseases with a mitochondrial type of inheritance (mitochondrial diseases): optic nerve atrophy Leber, syndromes Lei(mitochondrial myoencephalopathy), MERRF (myoclonic epilepsy), dilated familial cardiomyopathy. Pedigree of a patient with a mitochondrial type of inheritance of pathology (optic nerve atrophy Leber) in four generations is shown in Fig. 4–13.
INSTALLATION insert the file “PF Fig 04 13 Pedigree with mitochondrial type of inheritance of the disease”
Rice.4–13 .Pedigree with a mitochondrial type of inheritance of the disease. Circle - female gender, square - male gender, dark circle and / or square - sick.
Examples of monogenic diseases most commonly encountered in clinical practice
Phenylketonuria
All forms of phenylketonuria are the result of a deficiency of a number of enzymes. Their genes are transcribed in hepatocytes and are inherited in an autosomal recessive manner. The most common form of phenylketonuria occurs with mutations in the phenylalanine 4-monooxygenase gene (phenylalanine 4-hydroxylase, phenylalaninase). The most common type of mutation – single nucleotide substitutions (missense, nonsense mutations and mutations in splicing sites). The leading pathogenetic link of phenylketonuria – hyperphenylalaninemia with accumulation in tissues of toxic metabolic products (phenylpyruvic, phenylacetic, phenyllactic and other keto acids). This leads to damage to the central nervous system, impaired liver function, protein metabolism, lipo- and glycoproteins, and hormone metabolism.
Phenylketonuria appears: increased excitability and muscle hypertonicity, hyperreflexia and convulsions, signs of allergic dermatitis, hypopigmentation of the skin, hair, iris; "mouse" smell of urine and sweat, delayed psychomotor development. Untreated children develop microcephaly and mental retardation. This is another name for the disease. – phenylpyruvate oligophrenia.
Treatment of phenylketonuria is carried out with the help of diet therapy (with the exception or decrease in the content of phenylalanine in food). The diet must be observed from the moment of diagnosis (the first day after birth) and the content of phenylalanine in the blood must be monitored for at least 8–10 years. Hemophilia A (See the Hemophilia article in the Glossary of Terms appendix)
Syndrome Marfana
Syndrome frequency Marfana is in the range of 1:10,000–15,000. The syndrome is inherited in an autosomal dominant manner. Cause of the syndrome – fibrillin gene mutation ( FBN1). Approximately 70 mutations of this gene (mostly of the missense type) have been identified. Mutations of different exons of a gene FBN1 cause different changes in the phenotype, from moderately pronounced (subclinical) to severe.
Marfan syndrome appears generalized damage to the connective tissue (since fibrillin is widely represented in the matrix of the connective tissue of the skin, lungs, blood vessels, kidneys, muscles, cartilage, tendons, ligaments); skeletal damage, tall stature, disproportionately long limbs, arachnodactyly, lesions of the cardiovascular system, exfoliating aortic aneurysms, mitral valve prolapse, eye damage: dislocation or subluxation of the lens, trembling of the iris.
Hemoglobinopathies S
Hemoglobinopathy S (autosomal recessive inheritance) is common in the countries of the so-called malaria belt of the Earth. This is due to the fact that HbS heterozygotes are resistant to tropical malaria. In particular, HbS carriers are common in Transcaucasia and Central Asia; in Russia, the maximum frequency of heterozygous HbS carriers was noted in Dagestan.
The reason for HbS is the substitution of one base in 6 ‑ m triplet (missense mutation) ‑ globin chains. This results in the replacement of glutamic acid with valine. Such Hb has an extremely low solubility. Crystalline tactoids are formed intracellularly from HbS. They give the erythrocytes the shape of a sickle. Hence the name of the disease – "sickle cell anemia".
Heterozygous carriers of HbS are healthy under normal conditions, but with low pO 2 (caisson work, high altitude conditions, etc.) or hypoxemia (cardiac congenital malformations, respiratory failure, prolonged anesthesia, etc.), hemolytic anemia develops.
Homozygotes suffer from severe hemolytic anemia from 4 to 6 ‑ month old. As a result of thrombosis of capillaries or venules by sickle-shaped erythrocytes, trophic ulcers develop (often on the lower leg), abdominal pain, damage to the heart, eyes. Lesions of the osteoarticular system, hepatosplenomegaly are characteristic.
cystic fibrosis
Cystic fibrosis is a multiple lesion of the exocrine glands, accompanied by the accumulation and release of viscous secretions. Among newborns, the incidence of cystic fibrosis is 1:1500–1:2000. Cystic fibrosis is one of the most common monogenic diseases in Europe. Cystic fibrosis is inherited in an autosomal recessive manner. More than 130 mutant alleles are known; most common mutation – delF508. It leads to the absence of phenylalanine at position 508 of the transmembrane regulatory protein. Depending on the type of mutations and their localization, the function of the gene can be completely or partially impaired. At the same time, the regulation of the transfer of Cl - through the membranes of epithelial cells is upset (transport of Cl - is inhibited, and Na + increases).
The disease is characterized by the closure of the ducts of the glands with a viscous secretion, which is formed in connection with the increased resorption of Na + by the cells of the ducts of the exocrine glands. Often, cysts form in the ducts and inflammation develops. In a chronic course, an excess of connective tissue (sclerosis) develops in the glands. In newborns, bowel obstruction (meconium ileus) is often detected. Children most often develop the pulmonary or pulmonary-intestinal form of the disease. It is manifested by repeated bronchitis, pneumonia, pulmonary emphysema, as well as disorders of abdominal and parietal digestion, up to the development of malabsorption syndrome (malabsorption syndrome). With a long course, respiratory failure, cirrhosis of the liver, portal hypertension develop, often leading to death.
Human hereditary diseases- due to pathological mutations that are passed from generation to generation. These mutations can be localized both in the X or Y sex chromosomes, and in the normal ones. In the first case, the nature of the inheritance of diseases differs in men and women, in the second case, gender will not matter in the patterns of inheritance of genetic mutations. Hereditary diseases are divided into two groups : chromosomal and gene.
Genetic diseases, in turn, are divided into monogenic and multifactorial. The origin of the former depends on the presence of mutations in a particular gene. Mutations can disrupt the structure, increase or decrease the quantitative content of the protein encoded by the gene.
In many cases, patients do not show either the activity of the mutant protein or its immunological forms. As a result, the corresponding metabolic processes are disrupted, which, in turn, can lead to abnormal development or functioning of various organs and systems of the patient. Multifactorial diseases - due to the combined action of adverse environmental factors and genetic risk factors that form a hereditary predisposition to the disease. This group of diseases includes the vast majority of chronic human diseases affecting the cardiovascular, respiratory, endocrine and other systems. A number of infectious diseases can also be attributed to this group of diseases, sensitivity to which in many cases is also genetically determined.
With a certain degree of conditionality, multifactorial diseases can be divided into:
Congenital malformations
Common mental and nervous diseases
Common diseases of middle age.
CDF of multifactorial nature- cleft lip and palate, spinal hernia, pyloric stenosis, anencephaly and craniocerebral hernia, hip dislocation, hydrocephalus, hypospadias, clubfoot, bronchial asthma, diabetes mellitus, peptic ulcer of the stomach and duodenum, rheumatoid arthritis, collagenoses. Genetic diseases - this is a large group of diseases resulting from DNA damage at the gene level, used in relation to monogenic diseases. Examples:
Phenylketonuria - a violation of the conversion of phenylalanine to tyrosine due to a sharp decrease in the activity of phenylalanine hydroxylase
Alkaptonuria is a violation of tyrosine metabolism due to reduced activity of the homogentisinase enzyme and the accumulation of homotentisic acid in the tissues of the body
Oculocutaneous albinism - due to the lack of synthesis of the enzyme tyrosinase.
Niemann-Pick disease - decreased activity of the enzyme sphingomyelinase, degeneration of nerve cells and disruption of the nervous system
Gaucher disease is the accumulation of cerebrosides in the cells of the nervous and reticuloendothelial system, due to a deficiency of the enzyme glucocerebrosidase.
Marfan's syndrome spider fingers, arachnodactyly - damage to the connective tissue due to a mutation in the gene responsible for the synthesis of fibrillin.
Chromosomal diseases - include diseases caused by genomic mutations or structural changes in individual chromosomes. Chromosomal diseases result from mutations in the germ cells of one of the parents. Examples: Diseases caused by a violation of the number of autosomes of non-sex chromosomes
Down syndrome - trisomy on chromosome 21, signs include: dementia, growth retardation, characteristic appearance, changes in dermatoglyphics
Patau syndrome - trisomy on chromosome 13, characterized by multiple malformations, idiocy, often - polydactyly, violations of the structure of the genital organs, deafness; almost all patients do not live up to one year
Edwards syndrome - trisomy on chromosome 18, the lower jaw and mouth opening are small, the palpebral fissures are narrow and short, the auricles are deformed; 60% of children die before the age of 3 months, only 10% live up to a year, the main cause is respiratory arrest and disruption of the heart.
Diseases associated with a violation of the number of sex chromosomes
Shereshevsky-Turner syndrome - the absence of one X chromosome in women 45 XO due to a violation of the divergence of the sex chromosomes; the signs include short stature, sexual infantilism and infertility, various somatic disorders of micrognathia, a short neck, etc.
X-chromosome polysomy - includes trisomy karyoty 47, XXX, tetrasomy 48, XXXX, pentasomy 49, XXXXX, there is a slight decrease in intelligence, an increased likelihood of developing psychosis and schizophrenia with an unfavorable type of course
Y-chromosome polysomy - like X-chromosome polysomy, includes trisomy karyoty 47, XYY, tetrasomy 48, XYYY, pentasomy 49, XYYYY, clinical manifestations are also similar to X-chromosome polysomy
Klinefelter's syndrome - polysomy on X- and Y-chromosomes in boys 47, XXY; 48, XXYY and others, signs: eunuchoid body type, gynecomastia, weak hair growth on the face, in the armpits and on the pubis, sexual infantilism, infertility; mental development lags behind, but sometimes intelligence is normal.
Diseases caused by polyploidy triploidy, tetraploidy, etc.; the reason is a violation of the meiosis process due to a mutation, as a result of which the daughter sex cell receives a diploid 46 set of chromosomes instead of the haploid 23, that is, 69 chromosomes in men, the karyotype is 69, XYY, in women - 69, XXX; almost always fatal before birth.
Mitochondrial diseases- a group of hereditary diseases associated with defects in the functioning of mitochondria, leading to disruption of energy functions in eukaryotic cells, in particular in humans. Caused by genetic, structural, biochemical defects in mitochondria, leading to impaired tissue respiration. They are transmitted only through the female line to children of both sexes, since spermatozoa transfer half of the nuclear genome to the zygote, and the egg supplies both the second half of the genome and mitochondria.
Examples: In addition to the relatively common mitochondrial myopathy , meet
Mitochondrial diabetes accompanied by deafness DAD, MIDD,
MELAS syndrome is a combination that manifests itself at an early age, may be caused by a mutation in the mitochondrial MT-TL1 gene, but diabetes mellitus and deafness can be caused by both mitochondrial diseases and other causes.
Leber's hereditary optic neuropathy, characterized by loss of vision in early puberty
Wolff-Parkinson-White Syndrome
Multiple sclerosis and related diseases
Leigh's syndrome or subacute necrotizing encephalomyopathy: After the onset of normal postnatal development of the organism, the disease usually develops at the end of the first year of life, but sometimes manifests itself in adults. The disease is accompanied by a rapid loss of body functions and is characterized by convulsions, an impaired state of consciousness, dementia, and respiratory arrest.
| " |
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.
Generalized modern classification mitochondrial diseases highlights:
- 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.
Mutation can long time not manifest itself, 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 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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Some pedigrees of hereditary diseases cannot be explained by the typical Mendelian inheritance of nuclear genes. They are now known to be caused by mutations and exhibit maternal inheritance. Diseases caused by mutations in mitDNA exhibit many unusual features derived from the unique characteristics of mitochondrial biology and function.
Mitochondrial genome
Not all RNA and protein synthesized in the cell are encoded by the DNA of the nucleus; a small but important proportion is encoded in the genes of the mitochondrial genome. This genome consists of a 16.5 kilobase circular chromosome located in mitochondrial organelles rather than in the nucleus. Most cells contain at least 1000 mitDNA molecules distributed over hundreds of individual mitochondria. An important exception is the mature oocyte, which has over 100,000 copies of mitDNA, making up to one-third of the total DNA content in these cells.
Mitochondrial chromosome contains 37 genes. They encode 13 polypeptides - components of oxidative phosphorylation enzymes, two types of rRNA and 22 tRNAs necessary for the translation of mitochondrial gene transcripts. The remaining polypeptides of the oxidative phosphorylation complex are encoded by the nuclear genome.
IN mitDNA more than 100 different rearrangements and 100 different point mutations were found, disease-causing in humans, often affecting the central nervous system and the musculoskeletal system (for example, myoclonus epilepsy with "torn" red fibers - MERRF). Diseases caused by these mutations have a distinct mode of inheritance due to three unusual characteristics of mitochondria: replicative segregation, homoplasmy and heteroplasmy, and maternal inheritance.
Replicative segregation of the mitochondrial chromosome
First Unique Feature mitochondrial chromosome- lack of controlled segregation observed in mitosis and meiosis of 46 nuclear chromosomes. During cell division, numerous copies of mitDNA in each mitochondria of the cell are copied and randomly disperse into newly synthesized mitochondria. Mitochondria, in turn, are randomly distributed among daughter cells. This process is known as replicative segregation.
Homoplasmy and heteroplasmy of the mitochondrial chromosome
The second unique characteristic of genetics mitDNA occurs because most cells contain many copies of mitDNA molecules. When a mutation occurs in mitDNA, it is initially present in only one of the molecules in the mitochondria. During replicative segregation, the mitochondrion containing the mutant mitDNA produces multiple copies of the mutant molecule.
When dividing, a cell containing a mixture of normal and mutant mitochondrial DNA, can pass on to daughter cells very different proportions of mutant and wild mitDNA. One daughter cell can randomly obtain mitochondria containing a pure population of normal or a pure population of mutant mitochondrial DNA (a situation known as homoplasmy). In addition, a daughter cell can receive a mixture of mitochondria with and without a mutation (heteroplasmy).
Since the phenotypic expression of the mutation in mitDNA depends on the relative proportions of normal and mutant mitDNA in cells forming various tissues, incomplete penetrance, variable expressivity and pleiotropy are typical characteristics of mitochondrial diseases.
Maternal inheritance of mitochondrial DNA
Result defined by characteristics mitDNA genetics, is called maternal inheritance. Sperm mitochondria are usually absent in the embryo, so mitDNA is inherited from the mother. Thus, all children of a woman who is homoplasmic in a mitDNA mutation will inherit the mutation, while none of the offspring of a man carrying the same mutation will inherit the defective DNA.
maternal inheritance homoplasmic mitDNA mutation causing Leber's hereditary optic neuropathy.
Peculiarities maternal inheritance with heteroplasmy in the mother, additional characteristics of mitDNA genetics are identified that are of medical importance. First, the small number of mitDNA molecules in developing oocytes subsequently increases to the huge numbers seen in mature oocytes. This limitation, followed by the multiplication of mitDNA during oogenesis, characterizes the so-called “bottleneck” of mitochondrial genetics.
That is why the percentage variability mutant mitDNA molecules, found in the offspring of a mother with heteroplasmy, arises, at least in part, due to the increase in only a part of the mitochondrial chromosomes in oogenesis. One would expect that a mother with a high proportion of mutant mitDNA molecules would be more likely to produce eggs with a high proportion of mutant mitDNA molecules, and hence more clinically affected offspring, than a mother with a lower proportion. There is one exception to maternal inheritance when the mother has heteroplasmy for a deletion in mitDNA; for unknown reasons, the deletion mitDNA molecule is not usually passed on from clinically ill mothers to their children.
Although mitochondria are almost always inherited exclusively through mother, there is at least one example of paternal inheritance of mitDNA in patients with mitochondrial myopathy. Therefore, in patients with observed sporadic mitDNA mutations, the rare possibility of paternal mitDNA inheritance should be considered.
The exact definition of family pedigree is an important part of working with each patient. Pedigrees can show both typical Mendelian inheritance patterns and rarer ones caused by mitochondrial mutations and sexual mosaicism; or complex variants of family cases that do not correspond to any of the types of inheritance. Determination of the type of inheritance is important not only for establishing a diagnosis in the proband, it also identifies other individuals in the family who are at risk and need examination and counseling.
Despite the difficult cytogenetic and molecular analyzes used by geneticists, an accurate family history, including family pedigree, remains a fundamental tool for all clinicians and genetic consultants to use in planning individualized patient care.
Characterization of mitochondrial inheritance:
Women who are homoplasmic in the mutation pass this mutation on to all children; men with the same mutation do not.
Women, heteroplasmic for point mutations and duplications, pass them on to all children. The proportion of mutant mitochondria in the offspring, and therefore the risk of development and severity of the disease, can vary significantly depending on the proportion of mutant mitochondria in the mother, and also accidentally, due to the small number of mitochondria in the "bottleneck" during maturation of oocytes. Heteroplasmic deletions are usually not inherited.
The proportion of mutant mitochondria in different tissues of patients with heteroplasmic mutations can vary significantly, causing various manifestations of the disease in the same family with mitochondrial mutation heteroplasmy. Pleiotropism and variable expressivity are often observed in different patients in the same family.
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, Rosmedtekhnologii
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 that affect universal cell 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, electron transport in the respiratory chain (using enzyme complexes I-IV) and oxidative phosphorylation (enzyme complex V). Mitochondrial dysfunctions are among the most important (often early) stages of cell damage. These disorders lead to a lack of energy supply to cells, disruption of many other important metabolic processes, further development of cellular damage up to cell death. For a clinician, the assessment of the degree of mitochondrial dysfunction is essential both for the formation of ideas about the essence and degree of processes occurring at the tissue level, and for the development of a plan for therapeutic correction of the pathological condition.
The concept of "mitochondrial diseases" was formed in medicine at the end of the 20th century due to hereditary diseases discovered shortly before, the main etiopathogenetic factors of which are mutations in the genes responsible for the synthesis of mitochondrial proteins. First of all, diseases associated with mutations in mitochondrial DNA discovered in the early 1960s were studied. This DNA, which has a relatively simple structure and resembles the circular chromosome of bacteria, has been studied in detail. The complete primary structure of human mitochondrial DNA (mitDNA) was published in 1981), and already at the end of the 1980s, the leading role of its mutations in the development of a number of hereditary diseases was proved. The latter include Leber's hereditary optic nerve atrophy, NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), MERRF syndrome (myoclonus epilepsy with "torn" red fibers in skeletal muscles), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), 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 frequency 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 infantile myopathies, Alpers's, Ley's, Barth's, Menkes' diseases, syndromes of carnitine deficiency, some enzymes of the Krebs cycle and the respiratory chain of mitochondria). It can be assumed that their number should be much larger, since the genes encoding the information of 98% of mitochondrial proteins are located in the nucleus.
In general, it can be said that the study of diseases caused by hereditary disorders of mitochondrial functions has made a kind of revolution in modern ideas about 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 an effective diagnostic toolkit (clinical, biochemical, morphological and molecular genetic criteria for polysystemic mitochondrial insufficiency), which made it possible to assess polysystemic disorders of cellular energy metabolism.
As for psychiatry, already in the 30s of the twentieth century, data were obtained that in patients with schizophrenia, after exercise, the level of lactic acid sharply increases. Later, in the form of a formalized scientific assumption, the postulate appeared that some regulatory mechanisms of energy exchange are responsible for the lack of "mental 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 to every cell in the body - could be responsible for the highly specialized features of schizophrenia". However, the situation changed in 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 the consistent growth 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 included in the title carried a shade of exaggerated modesty. The amount of information provided in the article was so large, and the logic of the authors was so flawless that there was no longer any doubt about the prospects of "mitochondrial psychiatry".
To date, there are several groups of evidence for the involvement 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 sensitivity of tissues to insufficient ATP production leaves a significant imprint on the clinical picture of mitochondrial diseases. In this regard, the nervous tissue is primarily of interest as the most energy-dependent. From 40 to 60% of the energy of ATP in neurons is spent on maintaining the ion gradient on their outer shell and the transmission of the nerve impulse. Therefore, dysfunctions of the central nervous system in classical "mitochondrial diseases" are of paramount importance and give reason to call the main symptom complex "mitochondrial encephalomyopathies". Clinically, such brain disorders as mental retardation, convulsions and stroke-like episodes came to the fore. 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 personality or emotional changes, remain in the shadows.
The accumulation of information about mental disorders in mitochondrial diseases began to occur much later in comparison with the above disorders. Nevertheless, there is now a sufficient amount of evidence for 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 hereditary optic neuropathy.
Quite often the development of classical signs mitochondrial disease preceded by moderately severe mental disorders. Therefore, patients may initially be observed by psychiatrists. In these cases, other symptoms of mitochondrial disease (photophobia, vertigo, fatigue, muscle weakness, etc.) are sometimes regarded as psychosomatic disorders. The well-known researcher of mitochondrial pathology P. Chinnery, in an article written jointly with D. Turnbull, points out: “Psychiatric complications constantly accompany mitochondrial disease. They usually take the form of reactive depression ... We have repeatedly observed cases of severe depression and suicidal attempts even before (emphasis added by the authors of the article) the diagnosis was established.
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, here is 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 schizophrenia-like 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 a "mitochondrial" disease, but also in their relatives. In particular, a case is described when a disease based on a deletion of one nucleotide pair of mitDNA in the region of the transfer RNA gene first manifested itself in a boy's 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 confirmed diagnoses by molecular genetic studies. As a rule, personality disorders develop after cognitive impairment. A case of autism in a patient with a mitDNA point mutation in the region of the transfer RNA gene is described.
Common features characteristic of mitochondrial and psychiatric diseases
We are talking about a certain clinical similarity of some mental illnesses and mitochondrial syndromes, as well as common types of their inheritance.
First of all, attention is drawn to the data on the prevalence of cases of maternal inheritance of certain mental illnesses, in particular bipolar disorders. Such inheritance cannot be explained in terms 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 for maternal inheritance in patients with schizophrenia. True, in this respect there is an alternative explanation used in our context: it is assumed that this trend may be due to unequal conditions for patients of different sexes in the search for a partner.
An indirect confirmation of the connection between mitochondrial and some mental diseases is also a tendency to the cyclicity of their clinical manifestations. With diseases such as bipolar disorder, this is common knowledge. However, data on ultra-, circadian, and seasonal rhythms of clinical manifestations of dysenergetic states are now beginning to accumulate in mitochondriology as well. 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 be the result of mitochondrial dysfunction rather than a manifestation of “communicative distress”, “hypochondrial pattern” or “ secondary acquisition” (“secondary gain”)”. Sometimes such terms are used to refer to the phenomenon of somatization of mental disorders.
In conclusion, we point out one more similarity: an increase in white matter density determined using 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, the mention of signs of lactic acidosis and some other biochemical changes, indicating a violation of energy metabolism in schizophrenia, began to appear from the 30s of the twentieth century. But only starting from the 1990s, 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 published works, D. Ben-Shachar and D. Laifenfeld divided all 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) disturbances in 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 putamen. At the same time, it was noted that it was less pronounced in patients treated with antipsychotics, and therefore the authors considered it possible to talk about the normalization of mitochondrial processes in the brain under the influence of antipsychotic therapy. This gives reason to mention the article by N.S. Kolomeets and N.A. Uranova about mitochondrial hyperplasia in presynaptic axon terminals in the area of substantia nigra in schizophrenia.
L. Cavelier et al. , examining the autopsy material of the brain of patients with schizophrenia, revealed a decrease in the activity of the IV complex of the respiratory chain in the caudate nucleus.
These results allowed us to suggest a primary or secondary role of mitochondrial dysfunction in the pathogenesis of schizophrenia. However, the autopsy material studied was related 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 discovery of mitochondrial changes in various bodies and systems in mental and other diseases. With regard to the possible influence of 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 in patients with schizophrenia. This made it possible to speak about the polysystemic nature of mitochondrial insufficiency. S. Whatley et al. , in particular, showed that in the frontal cortex the activity of complex IV decreases, in the temporal cortex - 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 the activity of the intramitochondrial enzyme, citrate synthase, corresponded to the control values in all the studied areas, which gave grounds to speak about the specificity of the obtained results for schizophrenia.
In addition to the studies considered, one can cite the work carried out in 1999-2000. the work of J. Prince et al. who studied the activity of respiratory complexes in different parts of the brain of patients with schizophrenia. These authors found no signs of changes in the activity of complex I, but the activity of complex IV was reduced in the caudate nucleus. At the same time, the latter, as well as the activity of complex II, was increased in the shell and in the nucleus accumbens. Moreover, an 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 works cited above attributed the signs of energy metabolism disorders to the effects of neuroleptics. In 2002, very interesting data in this respect were published by A. Gardner et al. on mitochondrial enzymes and ATP production in muscle biopsy specimens from patients with schizophrenia 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 earlier conclusions made by L. Kung and R. Roberts.
In 2002, the results of another remarkable work were published. It studied the activity of complex I of the respiratory chain in the platelets of 113 patients with schizophrenia in comparison with 37 healthy ones. The patients were divided into three groups: group 1 - with an acute psychotic episode, group 2 - with a chronic active form, and group 3 - with residual schizophrenia. The results showed that the activity of complex I was significantly increased compared with the control in patients of groups 1 and 2 and decreased in patients of 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 in the study of flavoprotein subunits of complex I in the same RNA and protein material. The results of this study thus not only confirmed the high likelihood of multisystem mitochondrial failure in schizophrenia, but also allowed the authors to recommend appropriate laboratory methods for disease monitoring.
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 plays a significant role in the pathogenesis of schizophrenia. It has been found that dopamine can inhibit complex I activity and ATP production. At the same time, the activity of IV and V complexes does not change. It turned out that, unlike dopamine, norepinephrine and serotonin do not affect ATP production.
Noteworthy is the emphasis made in the above works 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 the functional regulation of energy metabolism 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 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 patients with schizophrenia, the researchers of this group showed the presence of a cytochrome b gene polymorphism different from the control.
In these years, a series of works by the group 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 of the sequences upscaled from control were related to mitochondrial genes. Was significantly increased, in particular, the expression of the mitochondrial gene of the 2nd subunit of cytochrome oxidase. Four other genes were related to mitochondrial ribosomal RNA.
Japanese researchers, examining 300 cases of schizophrenia, did not find signs of the 3243AG mutation (which causes a violation in complex I in MELAS syndrome). No increased mutation 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. found a mutation in the 12027 nucleotide pair of mitDNA (gene of the 4th subunit of complex I), which was present in male patients with schizophrenia and which was not in women.
Characterization of three nuclear genes of complex I was studied in the prefrontal and visual cortex of patients with schizophrenia by R. Karry et al. . They found that the transcription and translation of some subunits was reduced in the prefrontal cortex and increased in the visual cortex (the authors interpreted these data in accordance with the concept of "hypofrontality" in schizophrenia). In the study of genes (including genes for mitochondrial proteins) in the hippocampal tissue of patients with schizophrenia treated with antipsychotics, no changes were found.
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 drug effects 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 the temporal lobe of the brain of patients with schizophrenia was revealed.
Depression and Bipolar Affective Disorders
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. The same authors revealed a decrease in the level of phosphocreatine in the temporal lobe 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 signs were observed in patients with some mitochondrial diseases.
With regard to molecular genetic data, it should immediately be noted that the results of a number of studies indicate the absence of evidence for 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 the difference in its haplotypes in patients with bipolar disorders and those examined from the control group, revealed some mutations characteristic of the former, in particular, in positions 5178 and 10398 - both positions are in the zone of complex I genes.
There are reports of the presence of mutations in the genes of complex I, not only in mitochondrial, but also in nuclear ones. So, in cultures of lymphoblastoid cells obtained from patients with bipolar disorders, a mutation was found in the NDUFV2 gene, localized on the 18th chromosome (18p11), and encoding one of the subunits of complex I. MitDNA sequencing of patients with bipolar disorders revealed a characteristic mutation at position 3644 of the ND1 subunit gene, which also belongs to complex I. An increase in the level of translation (but not transcription) has been found for some subunits of complex I in the visual cortex of patients with bipolar disorder. Among other studies, we will cite two studies in which the genes of the respiratory chain were investigated and their molecular genetic disorders 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 disorders of mitochondrial enzymes and a decrease in the level of ATP production in skeletal muscle tissue were revealed, while a significant correlation was found between the degree of decrease in ATP production and clinical manifestations mental disorder.
Other mental disorders
There is little research on mitochondrial dysfunction in other psychiatric disorders. Some of them were mentioned in the previous sections of the review. Here, we specifically mention the work of P. Filipek et al. , which described 2 children with autism and a mutation in the 15th chromosome, in the region 15q11-q13. Both children had 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 regarding 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 illnesses as an increased frequency of cases of maternal inheritance, which may indirectly indicate the involvement of mitochondrial pathology in their pathogenesis. However, there is more convincing evidence for 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, all of whom came from an extended family with maternal transmission of bipolar disorder. 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 people was found. At the same time, we can note the coincidence of data on position 10398 with the already mentioned data of Japanese authors, who suggested that 10398A mitDNA polymorphism is a risk factor for the development of bipolar disorders.
The most significant genealogical proof of the role of mitochondrial dysfunctions in the development of mental disorders is the fact that patients with classic mitochondrial diseases have relatives (more often on the maternal side) with moderate mental disorders. Anxiety and depression are often mentioned among such 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 conducted an anonymous survey of patients with mitochondrial diseases, as well as their family members, for 12 months. Among the questions were related to the state of health of the parents and close relatives of patients (on the paternal and maternal lines). Thus, 55 families (Group 1) with a suspected maternal and 111 families (Group 2) with a suspected non-maternal mode of inheritance of mitochondrial disease were studied. As a result, relatives of patients on the maternal side, compared with the paternal side, showed a higher incidence of several pathological conditions. Among them, along with migraines and irritable bowel syndrome, was depression. In group 1, intestinal dysfunctions, migraine and depression were observed in a larger percentage of mothers from the surveyed families - 60, 54 and 51%, respectively; in the 2nd group - 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
Effect of drugs used in psychiatry on mitochondrial function
In the previous sections of the review, we have already touched briefly on therapy issues. 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 areas of the brain, can uncouple oxidation and phosphorylation, reduce the activity of complex I and ATPase, lower the level of utilization ATP. However, the interpretation of 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 neuroleptics. In the previous sections of the review, we also present works that testify to 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 (though only at high doses) were revealed in an experimental study of serotonin reuptake inhibitors.
Lithium, widely used in the treatment of bipolar disorders, also, apparently, can have a positive effect on the processes of cellular energy metabolism. It competes with sodium ions, participating in the regulation of calcium pumps in mitochondria. A. Gardner and R. Boles in their review quote T. Gunter, a well-known specialist in mitochondrial calcium metabolism, 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 hypothesized to reduce the activation of the apoptotic cascade.
A. Gardner and R. Boles cite in the above review a lot of indirect clinical evidence of the positive effect of psychotropic drugs on symptoms, presumably dependent on dysenergy processes. Thus, intravenous administration of chlorpromazine and other antipsychotics reduces migraine headache. The effectiveness 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 neuralgia and other pain syndromes, including migraine. Lithium and serotonin reuptake inhibitors are also effective in the treatment of migraine.
Analyzing the rather contradictory information given above, we can conclude that psychotropic drugs are undoubtedly capable of influencing the processes of brain energy exchange and mitochondrial activity. Moreover, this influence is not uniquely stimulating or inhibitory, but rather “regulating”. At the same time, it can be different in neurons of different parts of the brain.
The foregoing suggests that the lack of energy in the brain, perhaps, primarily concerns areas especially affected by the pathological process.
The effectiveness of energotropic drugs in 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 message of T. Suzuki et al. deserves attention in the first place. about a patient with schizophrenia-like disorders on the background of the MELAS syndrome. After the application of coenzyme Q10 and nicotinic acid, the patient's mutism disappeared for several days. There is also a paper that reports the success of dichloroacetate (often used in "mitochondrial medicine" to reduce lactate levels) in a 19-year-old man with MELAS syndrome, in relation to the effect on the picture of delirium with auditory and visual hallucinations.
The literature also contains a description of the history of a patient with the MELAS syndrome with a detected point mutation 3243 mitDNA. This patient developed psychosis with auditory hallucinations and delusions of persecution, which was managed within a week with low doses of haloperidol. However, he later 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 stopped headaches, tinnitus and psychotic episodes.
There are also reports on the effectiveness of energy-tropic therapy in patients with mental illness. Thus, a 23-year-old patient with treatment-resistant depression was described, the severity of which significantly decreased after a 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 proved 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.
On the basis of the above data, it can be argued that the need has come to combine the efforts of psychiatrists and specialists dealing with mitochondrial diseases, aimed both at studying the dysenergy bases of disorders of higher nervous activity, and at analyzing the psychopathological manifestations of diseases associated with disorders of cellular energy metabolism. 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 corresponding descriptions, a large place is occupied by cases with a detected mitDNA 3243AG mutation, a generally recognized cause of the development of the MELAS syndrome.
Literature