Multisystem nature of mitochondrial damage and diagnostic criteria of diseases

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Introduction. At the end of the 20th century, the study of mitochondrial diseases began. In previous periods, researchers believed that early mutations in mitochondrial DNA were a rare disease. Further study of these theoretical studies contributed to the identification of pathogenic mutations in one out of 200 newborns. Comparing the causes and the likelihood of mitochondrial diseases, we can conclude that this is an urgent problem in neuropediatrics. [3] Neuropsychological diseases of this type cause effects on many vital organs: the brain, skeletal muscles, and the heart. Mitochondria play a key role in both health and disease. Their function is not limited to energy production, but serves a variety of mechanisms, ranging from iron and calcium homeostasis to the production of hormones and neurotransmitters such as melatonin [5]. They provide and influence communication at all physical levels through interaction with other organelles, the nucleus, and the external environment. These studies marked the beginning of understanding the need for an in-depth study of this pathology.
The purpose of the work. To determine the leading role of mitochondria, to formulate the mechanism of development of mitochondrial diseases by reviewing the literature, based on the identification of the basic principles of diagnosis and treatment.
Materials and methods of research. Digital resources were used to search and analyze data in the framework of the study: Elibrary.Ru, CyberLeninka, Pubmed.

The results of the study. Mitochondria are the smallest organelles found in all cells, with the exception of red blood cells. They are responsible for the production of chemical energy in the form of adenosine triphosphate (ATP). These structures have their own DNA, and according to modern scientific theories, they originated from bacteria. Initially, these were free-living microorganisms that eventually "migrated" into the cells of the human body and began to have a positive effect on it, producing energy. Like bacterial DNA, mitochondrial DNA has a ring structure, which differs from the linear shape of the genetic material contained in the cell nucleus. Mitochondria play a significant role in the regulation of the DNA of the nucleus. Given their bacterial origin and unique DNA, they can be considered as part of the microflora of the human body. The very first mitochondria were described by the scientist Richard Altmann, and the term "mitochondria" was proposed by the German physician Karl Bend in 1897. In 1949, researchers Eugene Kennedy and Albert Leninger provided a complete understanding of the role of mitochondria as cell power stations. These organelles are able to convert carbohydrates into the energy needed to maintain most cellular functions. The energy that is generated during the reaction is called oxidative metabolism, burning oxygen. [1]
Unlike gorenje, mitochondrial respiration differs in that in the first case energy is accumulated in the form of a unique molecule of adenosine triphosphate (ATP), and in the second case it is released as a result of an uncontrolled reaction. The energy-rich ATP molecule can be transported to any part of the cell and release energy when interacting with certain enzymes. Some skeletal muscles, brain cells, kidneys, heart, and liver may contain up to thousands of mitochondria.
An important byproduct of mitochondrial function is the release of reactive oxygen species called "free radicals." They are involved in the regulation of apoptosis, a process aimed at destroying cells. Apoptosis is a critically important and necessary cell function. This process allows the body to effectively get rid of spontaneously emerging cancer cells. However, it also has its negative aspects. While the activation of destructive cell genes is often a positive thing, a malfunction of the mitochondria can lead to the "suicide" of healthy cells. This is the main mechanism contributing to the destruction of neurons in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Apoptosis occurs in every person's body throughout life and contributes to a general decrease in cognitive functions of the brain with age. It is interesting to note that cells without a nucleus can still go through the process of apoptosis. Thus, mitochondria play a crucial role in determining the fate of a cell: whether it should continue to exist or die. Thus, mitochondria are more than simple organelles that convert carbohydrates into energy.
The study of mitochondrial diseases makes it possible to identify them as a special group of hereditary pathologies, the activity of which is caused by a change in the functioning of mitochondria, cellular structures responsible for the production of energy in the form of ATP through the process of oxidative phosphorylation. Pathological processes in the work of mitochondria are caused by mutations in their DNA (mtDNA), as well as in nuclear DNA. DNA defects encode proteins used in mitochondrial metabolism. The result of the affected organs and tissues are energy-dependent tissues such as nerve and muscle. Clinical observations demonstrate that these diseases are among the most common hereditary neurological disorders. According to statistics, the frequency of mutations in the European population may occur in 1 person out of 400, but its phenotypic manifestation occurs only in 1 case out of 8000 people.
The medical literature describes cases of primary and secondary mitochondrial diseases that are caused by impaired oxidative phosphorylation (OP). Primary mitochondrial diseases are caused by mutation of genes in mtDNA and nuclear DNA (yDNA), which act as encoding subunits of respiratory complexes and ATP synthetase. Secondary ones, at the same time, are caused by mutations in nuclear genes that encode proteins involved in OP. An example of this is the occurrence that creates a change in the nuclear genes responsible for the synthesis of proteins formed by ribosomes, but are not able to damage these organelles directly. Mitochondrial dysfunction is associated with metabolic syndrome, neural diseases, cancer, cardiovascular and infectious diseases, as well as inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed [6].
Mitochondrial myopathies.
Mitochondrial myopathy can lead to dysfunction of oxidative phosphorylation (OP). There are several main symptoms in these patients:
1) Rapid fatigue along with severe endurance to physical exertion
2) The manifestation of multisystem damage
3) If the disease is transmitted from the mother, then a family history may manifest itself.
Thanks to light microscopy, it is possible to detect wavy red fibers (VCS) located in muscles that are associated with OP. They can be detected by coloring with trichrome according to Homory. Thanks to this method, it can be detected that abnormal fibers will turn red.
Mitochondrial neurogastrointestinal encephalomyopathy.
Mitochondrial neurogastrointestinal encephalomyopathy can occur both at a young age and in old age. This disease can be established due to impaired motility of the stomach and intestines, as well as diarrhea, vomiting. Another factor may be infection of the external muscles of the eyes. Although these symptoms are key, a person may also experience short stature, cardiomyopathy, and increased levels of lactic acid in the blood. Mitochondrial neurogastrointestinal encephalomyopathy is a heterogeneous autosomal recessive disease that leads to multiple deletions in the thymidine phosphorylase gene.
To treat this disease, doctors often use hemodialysis at least once a year.
Progressive external ophthalmoplegia with progressive ptosis.
PHN is one of the most common manifestations of mitochondrial myopathies. The disease usually develops unnoticed during adolescence and young adulthood. In most cases, there is symmetrical slow-increasing ptosis and limited mobility of the eyeballs in all directions, especially upward. The progression of the disease is slow. In all 10 described patients with "pure" PH, the absence of cytochrome-C oxidase was detected. Histochemical examination of the muscle biopsy showed the presence of wavy fibers. When stained with cytochrome C oxidase, a mosaic distribution of unpainted fibers was observed, including wavy red fibers that did not have the activity of this enzyme.
• Myogenic ptosis: myopathies affecting the bulbar muscles; orbital myositis, myositis of the upper eyelid muscle, polymyositis; potassium metabolism disorders; myasthenia gravis; botulism.
Neurogenic ptosis: diseases affecting the oculomotor nerve.
The disease has a genetic heterogeneity. More than half of patients with PN have single extensive deletions or duplications (or both) in mitochondrial DNA. In other patients, maternal PHN was associated with point mutations, most often in the mitochondrial tRNA gene.
Treatment of seven patients with PHN and Kerns-Sayre syndrome for one year using coenzyme Q10 at a dosage of 120 mg per day led to an improvement in neurological functions and a decrease in serum lactic and pyruvic acid levels after standard physical activity. [2]

Conclusion. Thus, mitochondria play a key role in cell biology and energy metabolism. These organelles are not only responsible for the production of ATP, but also participate in the regulation of metabolism, apoptosis and maintenance of cellular homeostasis. Their unique structure and their own DNA emphasize the evolutionary importance of mitochondria as symbiotic organisms. Like other structures, mitochondria are capable of pathological structural changes. Mitochondrial diseases are a complex group of genetic disorders associated with impaired mitochondrial function, which leads to insufficient energy production in cells. These diseases can manifest themselves in various forms and affect many body systems, especially those that require a lot of energy, such as the nervous and muscular systems. These pathologies are characterized by genetic and clinical heterogeneity. To establish a diagnosis of systemic mitochondrial diseases, there are certain diagnostic criteria for making a diagnosis.

About the authors

Boris Azarov

Воронежский государственный медицинский университет им. Н.Н. Бурденко

Email: azarovborisjd9045@mail.ru
ORCID iD: 0009-0002-5111-3155
Russian Federation, г. Воронеж, Студенческая 10

Zoya Afanasyevna Vorontsova

Воронежский государственный медицинский университет им. Н.Н. Бурденко

Author for correspondence.
Email: azarovborisjd9045@mail.ru
ORCID iD: 0000-0002-3610-2549
Russian Federation, г. Воронеж, ул. Студенческая 10

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