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Mitochondrial diseases (tsitopatiya)


Mitochondrial diseases — group of the hereditary diseases connected with the defects in functioning of mitochondrions leading to disturbances of power functions in cells an eukaryote, in particular, of the person.
Mitochondrial diseases are caused by the genetic, structural, biochemical defects of mitochondrions leading to disturbances of tissue respiration. They are given only in the female line to children of both floors as spermatozoa transfer to a zygote a half of a nuclear genome, and the ovum delivers both the second half of a genome, and a mitochondrion. Pathological disturbances of cellular energy balance can be shown in the form of defects of various links in a tricarbonic acid cycle, in a respiratory chain, beta oxidation processes etc.

Not all enzymes and other regulators necessary for effective functioning of mitochondrions are coded by mitochondrial DNA. The most part of mitochondrial functions is controlled by nuclear.

It is possible to allocate two groups of mitochondrial diseases:

The pronounced hereditary syndromes caused by mutations of the genes responsible for mitochondrial proteins (Bart's syndrome, Kearns-Seyra's syndrome, Pearson's syndrome, MELAS syndrome, a syndrome of MERRF and others).

The secondary mitochondrial diseases including disturbance of cellular power exchange as an important link of formation of a pathogeny (a disease of connecting fabric, a syndrome of chronic fatigue, a glycogenosis, a cardiomyopathy, migraine, a liver failure, a pancytopenia, and also a hypoparathyrosis, diabetes, rickets and others).

Строение митохондрии

Mitochondrion structure

Reasons of mitochondrial diseases:

Damage of mitochondrions generally arises  because of influence of the reactive forms of oxygen (RFO). Now consider that the majority of RFK is formed by complexes I and III probably owing to release of electrons under the influence of NAD-N and FAD-N in TsPE. Mitochondrions use about 85% of the oxygen consumed by a cell in the course of formation of ATP.  During normal process  of OF from 0.4% to 4.0% of all used oxygen it will be transformed in mitochondrions to superoxidic radicals (O2-). Superoxide is transformed to hydrogen peroxide (H2O2) by means of detoxication enzymes -  a manganese superoxide scavenger (Mn-SOD) or zinc / медь-superoxide dismutases (Cu/Zn of SOD), - and then to water with the help glutathione peroxidases (GP) or a peroksidredoksin of III (PR III). However, if these enzymes are not capable  to convert quickly enough RFK, such as radical superoxide, to water, there is an oxidative damage and accumulates in mitochondrions.  Glutathione in PR is one of the main antioxidants in an organism. Glutathione represents the tripeptide containing a glutamine, glycine and cysteine. GP demands selenium as a cofactor.

It is shown, hundred in vitro superoxide damages the iron-sulfur cluster which is in in an active center of aconitase, a fertent of cycle TKK. Because of it iron reacts with H2O2 with education of hydroxylic radicals through Fenton reaction. Besides, nitrogen oxide (NO) is formed in mitochondrions by means of mitochondrial synthase of nitrogen oxide (МтСОА), and also freely diffuses in a mitochondrion from cytosol. NO reacts with O2 with education of other radical - peroxynitrite (ONOO-). Together these two radicals and other radicals can put essential damage to mitochondrions and other components of a cell.

In mitochondrions elements which are especially subject to influence of free radicals are lipids, proteins, oxidation-reduction enzymes and мтДНК. Direct damage of mitochondrial proteins reduces their affinity to substrates or coenzymes and thus break their function. The problem is complicated by the fact that if damage of a mitochondrion happened, then function of a mitochondrion can be compromised with increase in requirements of a cell for processes of a reparation of energy. Mitochondrial dysfunction can lead to chain process at which mitochondrial damage involves additional damage.

The complex I is especially sensitive to influence of nitrogen oxide (NO). At animals to whom natural and synthetic antagonists of a complex I entered death of neurons is, as a rule, observed. Dysfunction of a complex I was associated with hereditary optical neuropathy of Leber, Parkinson's disease and other neurodegenerative states.

The hyperglycemia induces formation of superoxide in mitochondrions endothelial cells which is an important mediator of diabetic complications, such as cordial vascular diseases. Formation of superoxide in an endothelium also promotes development of atherosclerosis, hypertensia, heart failure, aging, sepsis, ischemic - reperfusion damages and a hypercholesterolemia.

Inflammation mediators, such as factor of a necrosis of tumors α (ФНОα) were connected by in vitro with mitochondrial dysfunction  and increased formation of FRK. In model of congestive heart failure  addition ФНОα to culture of cardiomyocytes increased education RFK and a hypertrophy of myocytes. ФНОα causes mitochondrial dysfunction  by recovery of activity of a complex III in TsPE, increasing formation of RFK and damage мтДНК.

Deficit of nutrients or their surplus can also lead to mitochondrial dysfunction. Vitamins, minerals and other metabolites work as necessary cofactors for synthesis and functioning of mitochondrial enzymes and other components which support function of mitochondrions, and the diet with a lack of microcomponents can  accelerate aging of mitochondrions and promote a neurodegeneration. For example, the enzymes participating in a synthesis chain gem demand enough a pyridoxine, iron, copper, zinc and Riboflavinum. The lack of the nutrients necessary for what - or components of cycle TKK or TsPE, can lead to increase in formation of free radicals and damage мтДНК.

It is well known that the lack of nutrients is the eurysynusic reason of a pathogeny of many diseases and is the main subject of a dispute in health care.  A lack of iron the chief intermediary in development of the general load of the diseases affecting about 2 billion people, preferential women and children. It is the most widespread type of deficit of nutrients. The low status of content of iron reduces activity of mitochondrions  by switching off of a complex IV and increase  in an oxidative stress. The mechanisms which are the cornerstone of process of influence of deficit of nutrients (and in certain cases surplus as at an overload iron) on emergence, development and progressing of the diseases arising owing to disturbance of mitochondrial functions are so far already studied.

Inheritance of mitochondrial diseases:

Mitochondrions are inherited differently, than nuclear genes. Nuclear genes in each somatic cell are usually presented by two alleles (except for the majority of the genes linked to a floor at a heterogametic sex). One allele is inherited from the father, another from mother. However mitochondrions contain own DNA, and each mitochondrion of the person usually contains from 5 to 10 copies of ring molecule DNA (see Geteroplazmiya), and all mitochondrions are inherited from mother. When the mitochondrion shares, copies of DNA are in a random way distributed between her descendants. If only one of initial molecules DNA contains a mutation, as a result of accidental distribution such mutant molecules can collect in some mitochondrions. The mitochondrial disease begins to be shown while noticeable number of mitochondrions in many cells of this fabric acquire mutant copies of DNA (a threshold expression).

Mutations in mitochondrial DNA occur, for various reasons, much more more often than in nuclear. It means that mitochondrial diseases are rather often shown because of the natural again arising mutations. Sometimes rate of a mutirovaniye increases because of mutations in the nuclear genes coding enzymes which control DNA replication of mitochondrions.

Генетические аспекты митохондриальных болезней

Genetic aspects of mitochondrial diseases

Symptoms of mitochondrial diseases:

Effects of mitochondrial diseases are very different. Because of various distribution of defective mitochondrions in different bodies the mutation at one person can lead to a liver disease, and at another — to a brain disease. The size of manifestation of defect can be big or small, and it can significantly change, slowly increasing in time. Some small defects result only in inability of the patient to maintain the exercise stress corresponding to his age and are not followed by serious painful manifestations. Other defects can be more dangerous, leading to serious pathology.

Generally mitochondrial diseases are shown stronger at localization of defective mitochondrions in muscles, a brain, nervous tissue as these bodies demand most of all energy for performance of the corresponding functions.

In spite of the fact that course of mitochondrial diseases strongly differ at different patients, on the basis of the general symptoms and specific mutations causing a disease several main classes of these diseases are allocated.

In addition to rather widespread mitochondrial myopathy, meet:

1. The mitochondrial diabetes mellitus which is followed by deafness (DAD, MIDD, MELAS syndrome) is the combination which is shown at early age, MT-TL1 can be caused by a mutation of a mitochondrial gene, but the diabetes mellitus and deafness can be caused by both mitochondrial diseases, and other reasons;

2. Hereditary optical neuropathy of Leber, characterized by loss of sight in the early pubertal period;

3. WPW-syndrome;

4. Multiple sclerosis and similar to it diseases;

5. Syndrome Lea (Leigh) or subacute necrotizing entsefalomiopatiya: after initial normal post-natal development the disease is shown usually at the end of the first year of life, sometimes — at adult age. The disease is followed by bystry loss of functions of an organism and is characterized by spasms, the broken condition of consciousness, dementia, an apnoea;

6. Neuropathy, ataxy, retinitis pigmentos and ptosis: the progressing symptoms of neuropathy, an ataxy, tunnel sight and loss of sight, a ptosis, dementia;

7. Mitochondrial neyrogastrointenstinalny encephalopathy: gastrointestinal pseudo-obstruction and a cachexia, neuropathy, encephalopathy with changes of white matter of a brain.

Treatment of mitochondrial diseases:

Now treatment of mitochondrial diseases is in a development stage, but as a widespread therapeutic method serves symptomatic prevention by means of vitamins. In particular, in treatment of a syndrome of MELAS at a number of patients were effective a coenzyme of Q which is applied as a cytoprotector and antioxidant at cardiomyopathies and chronic heart failure, Riboflavinum and niacinamide. Also as one of methods pyruvates are applied.

Now experimental works on studying of a possibility of extracorporal (in vitro) fertilization with use of a himerny ovum which kernel is received from the patient's ovum with a mitochondrial disease, and cytoplasm from other ovum from the woman with normally functioning mitochondrions (replacement of a kernel) are carried out.

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