Mitochondria: Aging, Metabolic Syndrome and Cardiovascular Diseases. Formation of a New Paradigm

Cardiovascular diseases are among the major causes of mortality among aged people in most developed countries. Oxidative stress, which causes mutations of mitochondrial DNA and mitochondrial dysfunctions, was considered as the main mechanism of heart failure and other pathologies of old age. However, in recent years the prior paradigm of mechanisms of aging, oxidative stress and antioxidative defense was questioned and in some aspects even turned out to be wrong. In this review, we discuss the new data that led to the need to reconsider paradigms. We show that although the mitochondrial free radical theory of aging remains valid, the radical responsible for the aging is the protonated form of the superoxide radical, namely perhydroxyl radical, which was largely ignored all previous years. Perhydroxyl radical initiates the isoprostane pathway of lipid peroxidation (IPLP) of polyunsaturated fatty acids, which are part of the phospholipid core of the mitochondrial inner membrane. IPLP was discovered 30 years ago by Roberts and Morrow at the Vanderbilt University, but the mechanism of its initiation remained unknown. The IPLP causes formation of the racemic mixture of hundreds of biologically active products, named isoprostanes, and highly toxic molecules, first of all isolevuglandins. We distinguish two types of damages caused by IPLP during aging. The first one is associated with oxidative damages to cardiolipin and phosphatidylethanolamine (PEA), which result in disruption of polyenzymatic complexes of the oxidative phosphorylation system. The second type of dysfunctions is caused by the direct actions of toxic products on the lysine-containing proteins and PEA. To this type of mitochondrial damages evidently belongs the oxidative damage of the mitochondrial DNA polymerase, which results in a 20-fold increase in mutations of mitochondrial mtDNA.

1. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009; 2(5-6): 231-237. doi: 10.1242/dmm.001180

2. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007; 92(2): 399-404. doi: 10.1210/jc.2006-0513

3. Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev. 2002; 7(2): 115-130. doi: 10.1023/a:1015320423577

4. Schaper J, Meiser E, Stammler G. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circ Res. 1985; 56(3): 377-391. doi: 10.1161/01.RES.56.3.377

5. Gurin AM. Structural and functional features of the human cardiac muscle tissue. Sovremennye naukoemkie tekhnologii. 2009; 11(Suppl.): 28-40. (In Russ.)

6. Opie LH, Lopaschuk GD. Fuels: aerobic and anaerobic metabolism. In: Opie LH (ed.) Heart Physiology: From Cell to Circulation. Philadelphia: Lippincott Williams & Wilkins; 2004. 306-354.

7. Rolfe DFS, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev. 1997; 77(3): 731-758. doi: 10.1152/physrev.1997.77.3.731

8. Gonzalez-Freire M, de Cabo R, Bernier M, Sollott SJ, Fabbri E, Navas P, et al. Reconsidering the role of mitochondria in aging. J Gerontol A Biol Sci Med Sci. 2015; 70(11): 1334-1342. doi: 10.1093/gerona/glv070

9. Panov AV. Synergistic oxidation of fatty acids, glucose and amino acids metabolites by isolated rat heart mitochondria. EC Cardiology. 2018; 5(4): 198-208.

10. Panov AV, Dikalov SI. The mitochondrial metabolism and the age-associated cardiovascular diseases. EC Cardiology. 2018; 5(11): 750-769.

11. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003; 88(6): 2404-2411. doi: 10.1210/jc.2003-030242

12. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007; 92(2): 399-404. doi: 10.1210/jc.2006-0513

13. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998; 78(2): 547-581. doi: 10.1152/physrev.1998.78.2.547

14. Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci. 2006; 1067(1): 10-21. doi: 10.1196/annals.1354.003

15. Ryzhkova AI, Sazonova MA, Sinyov VV, Galitsyna EV, Chicheva MM, Melnichenko AA, et al. Mitochondrial diseases caused by mtDNA mutations: a mini-review. Ther Clin Risk Manag. 2018; 14: 1933-1942. doi: 10.2147/TCRM.S154863

16. Volobueva A, Grechko A, Yet S-F, Sobenin I, Orekhov A. Changes in mitochondrial genome associated with predisposition to atherosclerosis and related disease. Biomolecules. 2019; 9(8): 377. doi: 10.3390/biom9080377

17. Pinto M, Moraes CT. Mechanisms linking mtDNA damage and aging. Free Radic Biol Med. 2015; 85: 250-258. doi: 10.1016/j.freeradbiomed.2015.05.005

18. Szczepanowska K, Trifunovic A. Origins of mtDNA mutations in ageing. Essays Biochem. 2017; 61(3): 325-337. doi: 10.1042/EBC20160090

19. DeBalsi KL, Hoff KE, Copeland WC. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev. 2017; 33: 89-104. doi: 10.1016/j.arr.2016.04.006

20. Chocron ES, Munkácsya E, Pickering AM. Cause or casualty: The role of mitochondrial DNA in aging and age associated disease. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(2): 285-297. doi: 10.1016/j.bbadis.2018.09.035

21. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009; 417(1): 1-13. doi: 10.1042/BJ20081386

22. Brand MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med. 2016; 100: 14-31. doi: 10.1016/j.freeradbiomed.2016.04.001

23. Sawyer DT, Valentine JS. How super is superoxide? Acc Chem Res. 1981; 14: 393-400. doi: 10.1021/ar00072a005

24. Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends. Endocrinol Metab. 2009; 20(8): 394-401. doi: 10.1016/j.tem.2009.04.004

25. Hernando-Rodriguez B, Artal-Sanz M. Mitochondrial quality control mechanisms and the PHB (prohibitin) complex. Cells. 2018; 7(12): 238. doi: 10.3390/cells7120238

26. Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsh T, Macho A. et al. Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med. 1996; 184(3): 1155- 1160. doi: 10.1084/jem.184.3.1155

27. Paradies G, Petrosillo G, Paradies V, Ruggiero FM. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium. 2009; 45(6): 643-650. doi: 10.1016/j.ceca.2009.03.012

28. Paradies G, Petrosillo G, Paradies V, Ruggiero FM. Mitochondrial dysfunction in brain aging: role of oxidative stress and cardiolipin. Neurochem Int. 2011; 58(4): 447-457. doi: 10.1016/j.neuint.2010.12.016

29. Brame CJ, Boutaud O, Davies SS, Yang T, Oates JA, Roden D, et al. Modification of proteins by isoketal-containing oxidized phospholipids. J Biol Chem. 2004; 279: 13447-13451. doi: 10.1074/jbc.M313349200

30. Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ, 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA. 1990; 87(23): 9383-9387. doi: 10.1073/pnas.87.23.9383

31. Jouhet J. Importance of the hexagonal lipid phase in biological membrane organization. Front Plant Sci. 2013; 4: 494. doi: 10.3389/fpls.2013.00494

32. Horvath SE, Daum G. Lipids of mitochondria. Prog Lipid Res. 2013; 52(4): 590-614. doi: 10.1016/j.plipres.2013.07.002

33. Haines TH. A new look at Cardiolipin. Biochim Biophys Acta. 2009; 1788(10): 1997-2002. doi: 10.1016/j.bbamem.2009.09.008

34. Sathappa M, Alder NN. The ionization properties of cardiolipin and its variants in model bilayers. Biochim Biophys Acta. 2016; 1858(6): 1362-1372. doi: 10.1016/j.bbamem.2016.03.007

35. Houtkooper RH, Vaz FM. Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci. 2008; 65(16): 2493-2506. doi: 10.1007/s00018-008-8030-5

36. Lewis RN, McElhaney RN. The physicochemical properties of cardiolipin bilayers and cardiolipin-containing lipid membranes. Biochim Biophys Acta. 2009; 1788(10): 2069-2079. doi: 10.1016/j.bbamem.2009.03.014

37. Beyer K, Klingenberg M. ADP/ATP carrier protein from beef heart mitochondria has high amounts of tightly bound cardiolipin, as revealed by 31P nuclear magnetic resonance. Biochemistry. 1985; 24(15): 3821-3826. doi: 10.1021/bi00336a001

38. van Meer G, de Kroon AI. Lipid map of the mammalian cell. J Cell Sci. 2011; 124(1): 5-8. doi: 10.1242/jcs.071233

39. Lee HJ, Mayette J, Rapoport SI, Bazinet RP. Selective remodeling of cardiolipin fatty acids in the aged rat heart. Lipids Health Dis. 2006; 5(1): 2. doi: 10.1186/1476-511X-5-2

40. Han X, Yang J, Yang K, Zhao Z, Abendschein DR, Gross RW. Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study. Biochemistry. 2007; 46(21): 6417-6428. doi: 10.1021/bi7004015

41. Morrow JD, Awad JA, Wu A, Zackert WE, Daniel VC, Roberts LJ, 2nd. Nonenzymatic free radical-catalyzed generation of thromboxane-like compounds (isothromboxanes) in vivo. J Biol Chem. 1996, 271(38): 23185-23190. doi: 10.1074/jbc.271.38.23185

42. Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1998; 273(22): 13605-13612. doi: 10.1074/jbc.273.22.13605

43. Wittig I, Schägger H. Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biophys Biochim Acta. 2009; 1787(6): 672-680. doi: 10.1016/j.bbabio.2008.12.016

44. Bultema JB, Braun HP, Boekema EJ, Kouril R. Megacomplex organization of the oxidative phosphorylation system by structural analysis of respiratory chain supercomplexes from tomato. Biochim Biophys Acta. 2009; 1787(1): 60-67. doi: 10.1016/j.bbabio.2008.10.010

45. Petersen MW, Skovenborg EL, Rask CU, Hoeg MD, Ornbol E, Schroder A. Physical comorbidity in patients with multiple functional somatic syndromes. A register-based case-control study. J Psychosom Res. 2018; 104: 22-28. doi: 10.1016/j.jpsychores.2017.11.005

46. Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1988; 273(22): 13605-13612. doi: 10.1074/jbc.273.22.13605

47. Morrow JD, Awad JA, Boss HJ, Blair IA, Roberts LJ. Noncyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc Natl Acad Sci USA. 1992; 89(22): 10721-10725. doi: 10.1073/pnas.89.22.10721

48. Brame CJ, Boutaud O, Davies SS, Yang T, Oates JA, Roden D, et al. Modification of proteins by isoketal-containing oxidized phospholipids. J Biol Chem. 2004; 279(14): 13447-13451. doi: 10.1074/jbc.M313349200

49. Musiek ES, Yin H, Milne GL, Morrow JD. Recent advances in the biochemistry and clinical relevance of the isoprostane pathway. Lipids. 2005; 40(10): 987-994. doi: 10.1007/s11745-005-1460-7

50. Montine TJ, Morrow JD. Fatty acid oxidation in the pathogenesis of Alzheimer’s disease. Am J Pathol. 2005; 166(5): 1283-1285. doi: 10.1016/S0002-9440(10)62347-4

51. Montuschi P, Barnes PJ, Roberts LJ. Isoprostanes: markers and mediators of oxidative stress. FASEB J. 2004; 18(15): 1791-1800. doi: 10.1096/fj.04-2330rev

52. Davies SS, Roberts LJ. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Rad Biol Med. 2011; 50(5): 559-566. doi: 10.1016/j.freeradbiomed.2010.11.023

53. Panov A.Perhydroxyl radical(HO2•)asinducerofthe isoprostane lipid peroxidation in mitochondria. Mol Biol. 2018; 52: 295-305. doi: 10.1134/S0026893318020097

54. Panov AV, Dikalov SI. Cardiolipin, perhydroxyl radicals and lipid peroxidation in mitochondrial dysfunctions and aging. Oxidative medicine and cellular longevity. Forthcoming 2020.

55. Bielski BH, Arudi RL, Sutherland MW. A study of the reactivity of HO2/O2- with unsaturated fatty acids. J Biol Chem. 1983; 258(8): 4759-4761.

56. Gebicki JM, Bielski BHJ. Comparison of the capacities of the perhydroxyl and the superoxide radicals to initiate chain oxidation of linoleic acid. J Am Chem Soc. 1981; 103: 7020-7022. doi: 10.1021/ja00413a066

57. De Grey ADNJ.HO2•theforgottenradical.DNA Cell Biology. 2002; 21(4): 251-257. doi: 10.1089/104454902753759672

58. Haines TH, Dencher NA. Cardiolipin: a proton trap for oxidative phosphorylation. FEBS Lett. 2002; 528(1-3): 35-39. doi: 10.1016/S0014-5793(02)03292-1

59. Arnarez C, Marrink SJ, Periole X. Identification of cardiolipin binding sites on cytochrome c oxidase at the entrance of proton channels. Sci Rep. 2013; 3: 1263. doi: 10.1038/srep01263

60. Bielski BHJ. Reevaluation of the spectral and kinetic properties of HO2• and O2• free radicals. Photochem Photobiol. 1978; 28(4-5): 645-649. doi: 10.1111/j.1751-1097.1978.tb06986.x

61. Barja G. The mitochondrial free radical theory of aging. Prog Mol Biol Transl Sci. 2014; 127: 1-27. doi: 10.1016/B978-0-12-394625-6.00001-5

62. Lambert AJ, Boysen HM, Buckingham JA, Yang T, Podlutsky A, Austad SN, et al. Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. Aging Cell. 2007; 6: 607-618. doi: 10.1111/j.1474-9726.2007.00312.x

63. Pamplona R, Barja B, Portero-Otin M. Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation? Ann N Y Acad Sci. 2002; 959: 475-490. doi: 10.1111/j.1749-6632.2002.tb02118.x

64. Naudi A, Jove M, Ayala V, Portero-Otı´n M, Barja G, Pamplona R. Regulation of membrane unsaturation as antioxidant adaptive mechanisms in long-lived animal species. Free Radic Antioxid. 2011; 1(3): 3-12. doi: 10.5530/ax.2011.3.2

65. Panov A. Mitochondrial production of perhydroxyl radical (HO2•) as inducer of aging and related pathologies. J Biochem Biophys. 2017; 1(1): 105.

66. Lennicke C, Cocheme HM. Redox signaling and ageing insights from Drosophila. Biochem Soc Trans. 2020; 48(2): 367-377. doi: 10.1042/BST20190052

67. Detienne G, De Haes W, Mergan L, Edwards SL, Temmerman L, Van Bael S. Beyond ROS clearance: Peroxiredoxins in stress signaling and aging. Ageing Res Rev. 2018; 44: 33-48. doi: 10.1016/j.arr.2018.03.005

68. Dikalov SI, Dikalova AE. Crosstalk between bitochondrial hyperacetylation and oxidative stress in vascular dysfunction and hypertension. Antioxid Redox Signal. 2019; 31(10): 710-721. doi: 10.1089/ars.2018.7632

69. Harman D. The aging process. Proc Natl Acad Sci USA. 1981; 78(11): 7124-7128. doi: 10.1073/pnas.78.11.7124

70. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009; 2(5-6): 231-237. doi: 10.1242/dmm.001180

71. Morris CW. Academic press dictionary of science and technology. California, San-Diego: Academic Press, Inc.; 1992.

72. Anderson AP, Luo X, Russell W, Yin YW. Oxidative damage diminishes mitochondrial DNA polymerase replication fidelity. Nucleic Acids Res. 2020; 48(2): 817-829. doi: 10.1093/nar/gkz1018