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Review Article Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging

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Review Article Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging Hindawi Oxidative Medicine and Cellular Longevity Volume 2020, Article ID 1323028, 14 pages https://doi.org/10.1155/2020/1323028 Review Article Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging Alexander V. Panov 1 and Sergey I. Dikalov2 1Federal Scientific Center for Family Health and Human Reproduction Problems, 16 Timiryasev str., Irkutsk, 664003, Russian Federation, Russia 2Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Correspondence should be addressed to Alexander V. Panov; [email protected] Received 16 April 2019; Accepted 19 February 2020; Published 9 September 2020 Guest Editor: Armen Y. Mulkidjanian Copyright © 2020 Alexander V. Panov and Sergey I. Dikalov. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitochondrial dysfunctions caused by oxidative stress are currently regarded as the main cause of aging. Accumulation of mutations and deletions of mtDNA is a hallmark of aging. So far, however, there is no evidence that most studied oxygen radicals are directly responsible for mutations of mtDNA. Oxidative damages to cardiolipin (CL) and phosphatidylethanolamine (PEA) are also hallmarks of oxidative stress, but the mechanisms of their damage remain obscure. CL is the only phospholipid present almost exclusively in the inner mitochondrial membrane (IMM) where it is responsible, together with PEA, for the maintenance of the superstructures of oxidative phosphorylation enzymes. CL has negative charges at the headgroups and due to specific localization at the negative curves of the IMM, it creates areas with the strong negative charge where local pH may be several units lower than in the surrounding bulk phases. At these sites with the higher acidity, the chance of protonation of the • superoxide radical (O ), generated by the respiratory chain, is much higher with the formation of the highly reactive 2 • • hydrophobic perhydroxyl radical (HO ). HO specifically reacts with the double bonds of polyunsaturated fatty acids (PUFA) 2 2 • initiating the isoprostane pathway of lipid peroxidation. Because HO2 is formed close to CL aggregates and PEA, it causes peroxidation of the linoleic acid in CL and also damages PEA. This causes disruption of the structural and functional integrity of the respirosomes and ATP synthase. We provide evidence that in elderly individuals with metabolic syndrome (MetS), fatty • • acids become the major substrates for production of ATP and this may increase several-fold generation of O and thus HO . • 2 2 We conclude that MetS accelerates aging and the mitochondrial dysfunctions are caused by the HO2 -induced direct oxidation of CL and the isoprostane pathway of lipid peroxidation (IPLP). The toxic products of IPLP damage not only PEA, but also mtDNA and OXPHOS proteins. This results in gradual disruption of the structural and functional integrity of mitochondria and cells. 1. Introduction workloads and associated metabolic activities. In the liver, which has relatively stable high rate of metabolism and high For the last five decades, the free radical theory of aging, first regeneration capacity, there was shown no significant accu- proposed by Harman [1–3], was regarded as one of the most mulation of mtDNA mutations with age [6]. For decades, important and investigated among other hypotheses of it was generally agreed that ROS-associated somatic muta- aging. Accumulation of mtDNA point mutations [4] and tions of mtDNA contribute to human aging and to the an exponential increase with age of mtDNA deletions [5] decline of energetic capabilities at higher age [5, 7]. were considered as important hallmarks of ageing and the In recent years, however, new experimental data have age-related diseases. Accumulation of mtDNA mutations discredited to some extent the original theory of direct partic- with increasing age was demonstrated mainly in heart, skel- ipation of free radicals in mtDNA mutations [8–10]. It has etal muscles, and brain, which undergo a high range of also been found that most common ROS species either are 2 Oxidative Medicine and Cellular Longevity H H H O O O O O O O + O O O P P H P P O O O O O O O O O O O O O O O O O O O O O O O O (a) (b) Figure 1: Cardiolipin structure. The figure depicts (for simplicity only) one of the cardiolipins–tetraoleilcardiolipin, and the two models headgroup ionization state at physiological pH 7.2. (a) Both phosphates have values of pKa1 of orthophosphoric acid. It is assumed that both phosphates ionize independently and the headgroup exists as a dianion. (b) Disparate pKa values of the two phosphates presume that the headgroup exists as a monoanion. The figure was adapted from [27]. Note: values for dissociation constants (pKa) of : рК : ирК : orthophosphoric acid: pKa1 =215, а2 =720, а3 =1235. • • not enough chemically active (O , NO) to initiate muta- of oxidative damages to mitochondrial enzymes and the mem- • 2 tions or excessively active ( OH) and have a too short life brane phospholipids, first of all phosphatidylethanolamine span in order to reach mtDNA [11, 12]. Several decades and cardiolipin, causes disruption of the structural and func- ago, researchers from the Vanderbilt University have discov- tional integrity of the respirosomes and ATP synthase. ered the isoprostane pathway of lipid peroxidation (IPLP), which results in the formation of prostaglandin-like com- 2. Properties of Cardiolipin pounds with enormous variations in molecular positional isomerism and stereoisomerism [13–16]. Considering the Cardiolipin (CL) is the only phospholipid that is present chemistry of IPLP, we have proposed the mechanism of ini- almost exclusively in the inner mitochondrial membrane of tiation of IPLP involving formation in the inner mitochon- all animals and in the plasma membrane of aerobic bacteria. • drial membrane of perhydroxyl radical (HO ), which is the That is in the membranes, where ATP is formed by the F F 2• 0 1 protonated form of superoxide radical (O2 ) [12, 17]. We ATP synthase [21]. CL is absent in the thylakoids of plants, suggest that the mechanisms of action of perhydroxyl radical where it is substituted by the plant sulfolipid (Sulfoquinovo- • (HO2 ) can explain the mechanism of initiation of the autox- syl dipalmitoylglycerol), probably because chloroplasts have idation of polyunsaturated fatty acids that are still part of the another isoform of ATP-synthase (CF0CF1) [22], and, most ’ • membrane s phospholipid. In addition, HO2 can be importantly, the reversed, as compared to mitochondria, ori- regarded as a “carrier” of the highly toxic hydroxyl radical entations of the energy-transforming enzymes, pH gradients, • ( OH) inside the hydrophobic core of the membrane and and electrical charges. The tight connection between the thus can oxidize cardiolipin. This can happen in spite the fact F0F1-ATP-syntahse and cardiolipin was proved by experi- that normally CL contains four linoleic acids with only two ments, in which facultative anaerobes were placed into the double bonds, which are not substrates for IPLP. In this oxygen-depleted atmosphere, and after a while, they lost review, we will focus on the roles of cardiolipin in oxidative not only F0F1-ATP-syntahse, but also cardiolipin [21]. stress due to the ability of this phospholipid to create, close The structure of the cardiolipin molecule was thoroughly to the surfaces of the inner mitochondrial membrane, the nar- described and discussed in [21, 23, 24]. The significance of row layer of structured water with low pH and high conduc- CL specifically for the energy-transforming membranes • tance for protons [18–20]. This facilitates conversion of O , comes from several intrinsic properties of the phospholipid, • 2 produced by the respiratory chain, into HO2 that initiate which originate from its unique structure (Figure 1). Due to IPLP [12, 17]. We consider that formation of toxic products, the conical form, CL, together with also conical phosphati- such as isolevuglandins (aka isoketals), produced by IPLP, as dylethanolamine (PEA), supports the superstructural organi- the major event in oxidative stress that is responsible for the zation of the respiratory chain and ATP synthase and allows slow but inevitable process of aging. The gradual accumulation accommodation of the multienzyme complexes into the Oxidative Medicine and Cellular Longevity 3 sharp curves of the inner membrane. Due to the conical form antennae, when the Coulomb radii of several cardioli- and strong negative charges at the headgroups, CL has the pins overlap and amplify a local negative charge propensity to form inverted hexagonal (HII) structures, (4) The mobility of the head group of CL is restricted which are essential for activation of the respiratory chain because of binding of the glycerol to two phosphati- enzymes and ATP synthesis by promoting binding and con- dates. Therefore, the self-shielding of phosphate ductance of protons through the hydrophobic milieu of the groups in CL is much lower than in other phospho- inner membrane [25–28] (Figure 1). lipids in the membrane. As a result, the phosphates Figure 1 does not reflect fully the fact that the shape of of cardiolipin on the surface of the inner membrane CL resembles that of a pyramid or cone with the broad base are easily accessible for interactions with proteins, and a very small head, which has the length of a glycerol peptides, and ions, as compared with other mem- molecule with three C atoms. In most cardiolipins, the fatty brane phospholipids [23]. The interactions of CL acids have usually two double bonds and therefore are with some proteins are so strong that CL was present strongly bend. For this reason, CL, similar to PEA, cannot in the crystal structures of the isolated mitochondrial form “normal” bilayer membranes [25, 27]. The two phos- proteins, for example, complex 3 and ANT [23].
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