Posted 05 June 2018 - 12:59 AM
Mitochondrial Production of Perhydroxyl Radical (HO2•) as Inducer of Aging and Age-Related Pathologies Panov A* Institute of Molecular Biology and Biophysics, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia *Corresponding author: Panov A, 3647 N. Kimberly Drive, Atlanta, GA, USA, Tel: 81-404-210-7031, E-mail: alexander.panov55@gmail.com Citation: Panov A (2017) Mitochondrial Production of Perhydroxyl Radical (HO2•) as Inducer of Aging and Age-Related Pathologies. J Biochem Biophy 1(1): 105
All organisms age, in the search of the universal mechanisms of aging Barja analyzed results obtained with various species of mammals and birds and concluded that only two known factors correlate in the right sense (inversely) with animal longevity in vertebrates: the long life span is associated with (a) low rates of mitochondrial reactive oxygen species production, and (b) low degree of fatty acid polyunsaturation of cellular membranes including the mitochondrial ones [Barja (2014) Prog Mol Biol Transl Sci. 127:1-27]. 20 years ago it was established that polyunsaturated fatty acids (PUFA), when still being esterified with the membrane phospholipids, undergo autoxidation with formation of products with large isomerism [Morrow et al. (1990). PNAS USA. 87: 9383-9387]. This process is known as the Isoprostane pathway of lipid peroxidation (IPLP), but the mechanism of IPLP initiation remained obscure. We propose that perhydroxyl radical (HO2•), which is a protonated form of the superoxide radical (O2•), initiates within the membrane a chain of reactions with formation of first H2O2, which in the hydrophobic environment undergoes homolytic fission producing two •OH radicals, thus very rapidly abstracting three H atoms from a PUFA. As a result, the HO2• molecule is converted to two molecules of water, and the molecule of a PUFA loses two double bonds, becomes highly unstable and undergoes peroxidation and random intramolecular re-arrangements causing a very large isomerism of the final products. Formation of O2•, and thus of HO2• radical, are inevitable consequences of the mitochondrial aerobic respiration, and because HO2• has very high affinity to PUFA, even the smallest amounts of this radical will cause damages to lipids, proteins and mtDNA. Our hypothesis is fully compatible with the conclusions made by Barja, and provides reasonable explanation for one of the important aging mechanisms. Abstract Keywords: Aging; Mitochondria; Oxidative stress; Superoxide radical; Perhydroxyl radical; Polyunsaturated fatty acids; Fatty acids autoxidation; Lipid peroxidation
Aging is the process of growing older or changing over time [1]. In other words, aging is the entire sequence of changes during ontogenesis of an individual organism during its lifetime. The major difference in the meanings of “ontogenesis” and “aging” is that the latter term, from the medical point of view, bears a strongly negative hint. Harman [2] defined aging as “progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death”. Knight [3] observed that “although the specific biologic basis of aging remains obscure, there is general agreement that its elucidation will be at the molecular
List of abbreviations: AA: Arachidonic Acid (C20:4 ω6); ANT: Aadenine Nucleotide Translocase; CL: Cardiolipin; СОХ1 and COX2: Cyclooxygenases; DHA: Docosahexaenoic acid (C22:6 ω3); DNA: Deoxyribonucleic acid; EPA: Eicosapentaenoic acid; FRTA: Free Radical Theory of Aging; GSH: Reduced Glutathione, HO2•: Perhydroxyl radical; IMM: Inner Mitochondrial Membrane; IsoPs: Isoprostanes; IPLP: Isoprostane pathway of lipid peroxidation, LOX: Lipoxygenases; LP: Lipid Peroxidation; MFRTA: Mitochondrial Free Radical Theory of Aging; mtDNA: mitochondrial deoxyribonucleic acid; mtROS: mitochondrial reactive oxygen species; •NO: nitric oxide radical; •NO2: Nitric dioxide radical; O2•: superoxide radical; •OH: hydroxyl radical; OMM: Outer mitochondrial membrane; •OONO: peroxynitrite radical; O2NOO•: peroxynitrate radical; PEA: Phosphatidylethanolamine; PGF2: Isoprostanes containing F-type prostane rings; PGs: Prostaglandins; PLA2: Ca-independent phospholipases A2; PUFA: Polyunsaturated Fatty Acids; RET: Reverse Electron Transport; ROS: Reactive Oxygen Species; SOD: Superoxide Dismutase; SOD1 (Cu,Zn-SOD1): Cytoplasmic SOD, SOD2 (MnSOD2) mitochondrial SOD