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The Role of Oxidative Stress and Mutations of Mitochondrial DNA at Aging, Age Pathology, and Apoptosis - Pharmacorrection by Mitochondria-Targeted Antioxidant Skq1

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The Role of Oxidative Stress and Mutations of Mitochondrial DNA at Aging, Age Pathology, and Apoptosis - Pharmacorrection by Mitochondria-Targeted Antioxidant Skq1 The Role of Oxidative Stress and Mutations of Mitochondrial DNA at Aging, Age Pathology, and Apoptosis - Pharmacorrection by Mitochondria-targeted Antioxidant SkQ1 Anatoly D. Gordienko1, Larysa V. Iakovlieva2, Oksana V. Tkachova2, Oksana Ya. Mishchenko3 1Department Pharmacology and Toxicology, Kharkiv State Zooveterinary Academy, Kharkiv, Ukraine, 2 3 REVIEW ARTICLE REVIEW Department of Pharmacoeconomics, National University of Pharmacy, Kharkiv, Ukraine, Department of Clinical Pharmacology, Institute of qualification improvement for pharmacists, Kharkiv, Ukraine Abstract There is presented the outcome analysis of numerous studies on the mechanisms of oxidative stress (OS) associated with increasing of the generation of reactive oxygen intermediate (ROI) in the electronic transport circuit of mitochondria, as well as the effect of ROI on the level of mutations in mitochondrial DNA (mtDNA). It is shown a fine sensibility of mtDNA to oxidative affections and mutations. The relation of age accumulation of mtDNA mutations with aging and life expectancy has been noted. It is also shown the relationship of OS with mtDNA mutations, apoptosis, diseases, and aging. It is considered a pharmacological way for the protection of ROI, aging, diseases, and prolonging life with the help of the antioxidant SkQ1, addressed directly to the mitochondria. Key words: Age-related pathologies, aging, apoptosis, genes, mitochondria DNA, mitochondria-targeted antioxidant SkQ1, mutations, oxidative stress, reactive oxygen intermediate THE HISTORY OF THE can lead to damages of biological molecules (proteins, [2] DEVELOPMENT OF THE FREE- lipids, nucleic acids, etc.). The accumulation of a number RADICAL THEORY of such damages in cells leads to disruption of their normal functioning, as well as to an increase in the probability of he free-radical theory of aging appeared death and the occurrence of various diseases. Initially, the FR in the middle of the 20th century. theory of aging was associated only with FR, as, for example, The foundations of this theory were О˙2 , but later the theory was extended to such reactive oxygen T intermediate (ROI) as hydrogen peroxide and peroxynitrite.[3] introduced almost simultaneously by two authors D. Harman in 1956 and M.M. Emanuel in 1958. The basis for its emergence was successful Under excessive formation of FR, oxidative stress (OS) may experiments for the continuation of life with the occur. As a result of the OS, free-radical theory accumulates help of antioxidants - phenol derivatives that damage at the cellular level, which leads to age-related tissue [4] inhibit free radical (FR) chemical reactions.[1] damage, aging, and carcinogenesis. For biological systems, the most important Address for correspondence: is oxygen FRs, in particular, the superoxide Oksana V Tkachova. Department of Pharmacoeconomics, ˙ National University of Pharmacy, 61168, Ukraine, anion radical (О 2), hydroxyl radical (OH), and nitric oxide (NO), the so-called reactive oxygen Kharkiv, Vlasenko Street. 22, 27. Tel.: +380990247214. intermediate (ROI). FRs are any molecules Е-mail: [email protected] or atoms that contain one or more unpaired Received: 02-10-2018 electrons at an external electronic level. By their Revised: 05-11-2018 nature, FR is very reactive and, being formed in Accepted: 17-11-2018 a cell as a result of some biological processes, Asian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1165 Gordienko, et al.: The Role of Oxidative Stress and Mutations of Mitochondrial DNA at Aging THE MITOCHONDRIAL THEORY OF lipids, proteins, and components of DNA, which contributes AGING to the accumulation of damaged macromolecules and organelles. The speed of organelle renewal decreases, the The modern theory of aging associates the process of aging accumulation of defective mitochondria increases. Aging with the OS in general. It is unlikely that aging is exclusively mitochondria gradually produce less and less ATP and more [17,22,23] associated with damages of FR; environmental factors and ROI. With age, the OS in the mitochondria plays a key the genetic background also play a significant role.[4] role in the development of the internal pathway of apoptosis. At aging and apoptosis, the same changes occur, such as a Under normal physiological conditions, the oxygen decrease in the mitochondrial membrane potential, increased consumed in the body in addition to the main respiratory levels of lipid peroxidation, oxidation of glutathione, and phase goes to the generation of FR, which occurs in many mitochondrial oxidative damage to DNA, mainly due to [25] cell organelles and with the participation of many enzymes. an elevation of OS. All of the abovementioned factors However, the greatest amount of ROI (about 90%) is formed contribute to the gradual reduction of mitochondrial [24,25] in the mitochondria. This is a consequence of oxidative respiratory function in laboratory animals and humans. phosphorylation - the process of energy generation in the form of ADP and ATP, accumulated on the inner membrane Mitochondria are the main organelles in the cell responsible of the mitochondria. It is shown that mitochondrial ROI plays for most of the FR reactions associated with the aging an important role in many oxidation-restorative signaling process. The life duration is determined by the level of FR in processes.[5-8] the mitochondria. It is believed that, with the age increment of a human due to OS, an imbalance appears between FR As a separate case of the FR theory, a mitochondrial theory production and antioxidant protection.[26] An increase in the of aging appeared, which is a modification of the free-radical level of oxidative damage of mtDNA, proteins, and lipids theory of aging, which states that aging in humans and animals and a decrease in the activity of the antioxidant system is due to the accumulation of damage in mitochondria and accompany the aging of organisms.[27,28] mitochondrial DNA (mtDNA).[9,10] As an intracellular source of ROI, mitochondria are the most vulnerable to direct attack The key role of mtDNA is evidently because mutations by the ROI. It has been shown that the levels of ROI-modified in mtDNA can accelerate the damage of the FR cell by proteins and lipid peroxides in mitochondria increase with introducing changes in the level of activity of components in age.[11-13] It should be noted that the membrane lipid of the electron transport chain. mitochondria, especially cardiolipin, which is important for mitochondrial bioenergetics,[14] lends itself to a high risk The malfunction of electronic transport chains and the of oxidative damage due to high levels of unsaturated fatty accumulation of FR subsequently lead to even more damage acids. Aging and OS are also associated with a decrease in the of mtDNA and ultimately stimulate mtDNA mutations. physical properties of internal membrane proteins, which are This “vicious circle” of mutations and generation of FR prone to OS damage.[15,16] The OS, as one of the mechanisms are considered the cause of cell aging.[29] The mitochondria of aging, contributes to the damage of membrane proteins, have its own apparatus for repairing mtDNA damages by which leads to a decrease in their physical properties and a exogenous and endogenous agents, where FR is the most violation of barrier properties of the membrane. common. MtDNA includes only 5% of the genetic material of the animal cell, but it contributes much more to cellular Since mtDNA encodes the polypeptides of the electron physiology than one can think, focusing only on this transmission network, any mtDNA mutations inevitably percentage. MtDNA, being in the immediate vicinity of the affect the entire electron transport chain, potentially changing site of the appearance of oxygen, is an available target for the functions of numerous nuclear genes involved in the undesirable effects of oxygen radicals. Oxidative damage to formation of the electron transfer chain.[5] mtDNA causes a change in nucleotide bases and other types of damage. The greatest harm is caused by 8-oxoguanine, A damage of mtDNA is usually much more extensive and lasts which accumulates in the DNA with age. Finally, defects longer than the damage to nuclear DNA.[7,13] The particular in the electron transport chain can produce a number of vulnerability of mtDNA is because it does not contain histone pleiotropic effects, since they affect the cellular energy.[30] proteins that are in nuclear DNA and performs a protective function. An unobstructed oxidative attack on mtDNA can The mtDNA mutations accumulate gradually throughout the slowly disrupt the functioning of mitochondria in the aging life and are directly responsible for the deficiency in oxidative organism.[16,17] Many studies have shown that there is the phosphorylation chains leading to the appearance of ROI. age-dependent nature of accumulation of mtDNA damage The primary importance of mitochondria in the aging process in the skeletal muscles, heart muscle, brain, and liver.[18-21] and in determining the lifespan is confirmed by the fact that Strengthening the OS with age leads to a decrease in the chemical mutagens and lipophilic carcinogens (for example, intensity of the mechanisms of degradation and neutralization polycyclic aromatic hydrocarbons) cause much more damage of not only the developed mitochondrial structures but also to mtDNA than nuclear mutations.[31] On this basis, in fact, it Asian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1166 Gordienko, et al.:
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