БИОХИМИЯ, 2018, том 83, вып. 10, с. 1572–1590

Гипотеза

УДК 577.24

Запускает ли окисление митохондриального кардиолипина цепь антиапоптотических реакций?

© 2018 А.Я. Мулкиджанян 1,2,3*, Д.Н. Шалаева 1, К.Г. Лямзаев 1, Б.В. Черняк 1

НИИ физико-химической биологии им. А.Н. Белозерского, Московский государственный университет имени М.В. Ломоносова, 119991 Москва, Россия

Московский государственный университет им. М.В. Ломоносова, факультет биоинженерии и биоинформатики, 119991 Москва, Россия

Оснабрюкский университет, физический факультет, 49069 Оснабрюк, Германия; электронная почта: amulkid@uos.de

Поступила в редакцию 07.12.2017
После доработки 16.05.2018

DOI: 10.1134/S0320972518100111

КЛЮЧЕВЫЕ СЛОВА: Активные формы кислорода, митохондриально-направленные антиоксиданты, перекисное окисление липидов, протонная утечка, мембранный потенциал, митофагия.

Аннотация

Окислительный стресс приводит к избирательному окислению кардиолипина (CL), липида с четырьмя жирнокислотными цепями, который специфичен для внутренней митохондриальной мембраны (IMM). Показано, что, в результате взаимодействия с окисленным CL, небольшой митохондриальный белок цитохром c обретает пероксидазную активность и способность окислять еще больше CL. В конечном счете, эта цепочка событий может приводить к образованию пор во внешней митохондриальной мембране (OMM) и высвобождению митохондриальных белков, включая цитохром c, в цитоплазму. Находясь в цитоплазме, молекулы цитохрома c могут инициировать сборку апоптосомы, которая запускает апоптоз – контролируемую смерть клетки. Из-за усиления сигнала в этом каскаде реакций даже случайное окисление одной молекулы кардиолипина образующимися в клетке активными формами кислорода (АФК) может, в конечном итоге, приводить к ликвидации всей клетки, если только это же окисление CL не запускает одновременно и цепь антиапоптотических реакций, разворачивающихся быстрее, чем CL-опосредованный апоптотический каскад. Данная работа посвящена реконструкции последовательности антиапопотозных реакций, запускаемых окислением CL. Исходя из структурных соображений, можно полагать, что ключевая функция CL в митохондриях и других сопрягающих мембранах заключается в предотвращении утечки протонов вдоль поверхности контакта мембранных белков. Поэтому окисление молекул кардиолипина должно увеличивать протонную проводимость богатых кардиолипином кластеров мембранных белков (CL-островков) и приводить к общему падению митохондриального мембранного потенциала (ММП). С одной стороны, падение ММП должно подавлять генерацию АФК и дальнейшее окисление CL во всей митохондрии. С другой стороны, падение ММП способно вызывать быструю фрагментацию митохондриальной сети и образование многих мелких митохондрий, только некоторые из которых будут содержать окисленные CL-островки. Фрагментация митохондриальной сети, предотвращая выход цитохрома c из здоровых митохондрий, должна препятствовать формированию апоптосом, давая возможность медленно работающим системам контроля качества удалить поврежденные митохондрии с окисленным CL. Из-за двух противоположно направленных путей регуляции, активируемых окислением CL, конечная судьба клетки, по-видимому, определяется балансом между CL-опосредованными проапоптотическими и антиапоптотическими реакциями. Поскольку этот баланс зависит от степени окисления CL, митохондиально-направленные антиоксиданты, специфически предотвращая окисление CL, по всей видимости, способствуют выживанию клеток в случае многих патологий.

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Финансирование

Работа выполнена при финансовой поддержке Российского научного фонда; анализ роли кардиолипина в защите от апоптоза проводился в рамках гранта № 17-14-01314, а биоинформационный и структурный анализ митохондриального АДФ/АТФ антипортера осуществлялся в рамках гранта № 14-50-00029. Авторы также благодарят за поддержку Deutsche Forschungsgemeinschaft, Федеральное министерство образования и исследований Германии, Немецкую службу академических обменов (DAAD) и Оснабрюкский университет.

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Конфликт интересов

У авторов отсутствует конфликт интересов в финансовой и в какой-либо иной сфере.

Соблюдение этических норм

Настоящая статья не содержит выполненных авторами исследований с участием людей или животных.

Список литературы

1. Zhivotovsky, B., Samali, A., and Orrenius, S. (2001) Determination of apoptosis and necrosis, Curr. Protoc. Toxicol., doi: 10.1002/0471140856.tx0202s00.

2. Skulachev, V.P. (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants, Q. Rev. Biophys., 29, 169–202.

3. Scherz-Shouval, R., and Elazar, Z. (2007) ROS, mitochondria and the regulation of autophagy, Trends Cell Biol., 17, 422–427.

4. Youle, R.J., and van der Bliek, A.M. (2012) Mitochondrial fission, fusion, and stress, Science, 337, 1062–1065.

5. Skulachev, V.P. (1996) Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell, FEBS Lett., 397, 7–10.

6. Hampton, M.B., Zhivotovsky, B., Slater, A.F., Burgess, D.H., and Orrenius, S. (1998) Importance of the redox state of cytochrome c during caspase activation in cytosolic extracts, Biochem. J., 329, 95–99.

7. Robertson, J.D., Gogvadze, V., Zhivotovsky, B., and Orrenius, S. (2000) Distinct pathways for stimulation of cytochrome c release by etoposide, J. Biol. Chem., 275, 32438–32443.

8. Zhivotovsky, B., Hanson, K.P., and Orrenius, S. (1998) Back to the future: the role of cytochrome c in cell death, Cell Death Differ., 5, 459–460.

9. Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X. (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c, Cell, 86, 147–157.

10. Skulachev, V.P. (1998) Cytochrome c in the apoptotic and antioxidant cascades, FEBS Lett., 423, 275–280.

11. Huttemann, M., Pecina, P., Rainbolt, M., Sanderson, T.H., Kagan, V.E., Samavati, L., Doan, J.W., and Lee, I. (2011) The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: from respiration to apoptosis, Mitochondrion, 11, 369–381.

12. Kagan, V.E., Chu, C.T., Tyurina, Y.Y., Cheikhi, A., and Bayir, H. (2014) Cardiolipin asymmetry, oxidation and signaling, Chem. Phys. Lipids, 179, 64–69.

13. Paradies, G., Paradies, V., De Benedictis, V., Ruggiero, F.M., and Petrosillo, G. (2014) Functional role of cardiolipin in mitochondrial bioenergetics, Biochim. Biophys. Acta, 1837, 408–417.

14. Skulachev, V.P., Anisimov, V.N., Antonenko, Y.N., Bakeeva, L.E., Chernyak, B.V., Erichev, V.P., Filenko, O.F., Kalinina, N.I., Kapelko, V.I., Kolosova, N.G., Kopnin, B.P., Korshunova, G.A., Lichinitser, M.R., Obukhova, L.A., Pasyukova, E.G., Pisarenko, O.I., Roginsky, V.A., Ruuge, E.K., Senin, II, Severina, II, Skulachev, M.V., Spivak, I.M., Tashlitsky, V.N., Tkachuk, V.A., Vyssokikh, M.Y., Yaguzhinsky, L.S., and Zorov, D.B. (2009) An attempt to prevent senescence: a mitochondrial approach, Biochim. Biophys. Acta, 1787, 437–461.

15. Ji, J., Kline, A.E., Amoscato, A., Samhan-Arias, A.K., Sparvero, L.J., Tyurin, V.A., Tyurina, Y.Y., Fink, B., Manole, M.D., Puccio, A.M., Okonkwo, D.O., Cheng, J.P., Alexander, H., Clark, R.S., Kochanek, P.M., Wipf, P., Kagan, V.E., and Bayir, H. (2012) Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury, Nat. Neurosci., 15, 1407–1413.

16. Barclay, L.R.C. (1992) Model biomembranes: quantitative studies of peroxidation, antioxidant action, partitioning, and oxidative stress, Can. J. Chem., 71, 1–16.

17. Niki, E., Yoshida, Y., Saito, Y., and Noguchi, N. (2005) Lipid peroxidation: mechanisms, inhibition, and biological effects, Biochem. Biophys. Res. Commun., 338, 668–676.

18. Kagan, V.E., Tyurin, V.A., Jiang, J., Tyurina, Y.Y., Ritov, V.B., Amoscato, A.A., Osipov, A.N., Belikova, N.A., Kapralov, A.A., Kini, V., Vlasova, I.I., Zhao, Q., Zou, M., Di, P., Svistunenko, D.A., Kurnikov, I.V., and Borisenko, G.G. (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors, Nat. Chem. Biol., 1, 223–232.

19. Kagan, V.E., Bayir, A., Bayir, H., Stoyanovsky, D., Borisenko, G.G., Tyurina, Y.Y., Wipf, P., Atkinson, J., Greenberger, J.S., Chapkin, R.S., and Belikova, N.A. (2009) Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: a new strategy in anti-apoptotic drug discovery, Mol. Nutr. Food Res., 53, 104–114.

20. Atkinson, J., Kapralov, A.A., Yanamala, N., Tyurina, Y.Y., Amoscato, A.A., Pearce, L., Peterson, J., Huang, Z., Jiang, J., Samhan-Arias, A.K., Maeda, A., Feng, W., Wasserloos, K., Belikova, N.A., Tyurin, V.A., Wang, H., Fletcher, J., Wang, Y., Vlasova, I.I., Klein-Seetharaman, J., Stoyanovsky, D.A., Bayir, H., Pitt, B.R., Epperly, M.W., Greenberger, J.S., and Kagan, V.E. (2011) A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death, Nat. Commun., 2, 497.

21. Jiang, J., Bakan, A., Kapralov, A.A., Silva, K.I., Huang, Z., Amoscato, A.A., Peterson, J., Garapati, V.K., Saxena, S., Bayir, H., Atkinson, J., Bahar, I., and Kagan, V.E. (2014) Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids, Free Radic. Biol. Med., 71, 221–230.

22. Gonzalvez, F., Pariselli, F., Dupaigne, P., Budihardjo, I., Lutter, M., Antonsson, B., Diolez, P., Manon, S., Martinou, J.C., Goubern, M., Wang, X., Bernard, S., and Petit, P.X. (2005) tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak, Cell Death Differ., 12, 614–626.

23. Chen, Q., Vazquez, E.J., Moghaddas, S., Hoppel, C.L., and Lesnefsky, E.J. (2003) Production of reactive oxygen species by mitochondria: central role of complex III, J. Biol. Chem., 278, 36027–36031.

24. Drose, S., and Brandt, U. (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex, J. Biol. Chem., 283, 21649–21654.

25. Grivennikova, V.G., and Vinogradov, A.D. (2013) Partitioning of superoxide and hydrogen peroxide production by mitochondrial respiratory complex I, Biochim. Biophys. Acta, 1827, 446–454.

26. Lapuente-Brun, E., Moreno-Loshuertos, R., Acin-Perez, R., Latorre-Pellicer, A., Colas, C., Balsa, E., Perales-Clemente, E., Quiros, P.M., Calvo, E., Rodriguez-Hernandez, M.A., Navas, P., Cruz, R., Carracedo, A., Lopez-Otin, C., Perez-Martos, A., Fernandez-Silva, P., Fernandez-Vizarra, E., and Enriquez, J.A. (2013) Supercomplex assembly determines electron flux in the mitochondrial electron transport chain, Science, 340, 1567–1570.

27. Gabai, V.L., and Sherman, M.Y. (2002) Invited review: interplay between molecular chaperones and signaling pathways in survival of heat shock, J. Appl. Physiol., 92, 1743–1748.

28. Israelachvili, J.N., Marcelja, S., and Horn, R.G. (1980) Physical principles of membrane organization, Q. Rev. Biophys., 13, 121–200.

29. Busch, K.B., Deckers-Hebestreit, G., Hanke, G.T., and Mulkidjanian, A.Y. (2013) Dynamics of bioenergetic microcompartments, Biol. Chem., 394, 163–188.

30. Cramer, W.A., and Knaff, D.B. (1990) Energy Transduction in Biological Membranes: A Textbook of Bioenergetics, Springer-Verlag.

31. Skulachev, V.P., Bogachev, A.V., and Kasparinsky, F.O. (2013) Principles of Bioenergetics, Springer, Berlin Heidelberg.

32. Pfeiffer, K., Gohil, V., Stuart, R.A., Hunte, C., Brandt, U., Greenberg, M.L., and Schagger, H. (2003) Cardiolipin stabilizes respiratory chain supercomplexes, J. Biol. Chem., 278, 52873–52880.

33. Mileykovskaya, E., and Dowhan, W. (2009) Cardiolipin membrane domains in prokaryotes and eukaryotes, Biochim. Biophys. Acta, 1788, 2084–2091.

34. Arias-Cartin, R., Grimaldi, S., Arnoux, P., Guigliarelli, B., and Magalon, A. (2012) Cardiolipin binding in bacterial respiratory complexes: Structural and functional implications, Biochim. Biophys. Acta, 1817, 1937–1949.

35. Musatov, A., and Sedlak, E. (2017) Role of cardiolipin in stability of integral membrane proteins, Biochimie, 142, 102–111.

36. Mileykovskaya, E., and Dowhan, W. (2014) Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes, Chem. Phys. Lipids, 179, 42–48.

37. Planas-Iglesias, J., Dwarakanath, H., Mohammadyani, D., Yanamala, N., Kagan, V.E., and Klein-Seetharaman, J. (2015) Cardiolipin interactions with proteins, Biophys. J., 109, 1282–1294.

38. Althoff, T., Mills, D.J., Popot, J.L., and Kuhlbrandt, W. (2011) Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1, EMBO J., 30, 4652–4664.

39. Letts, J.A., Fiedorczuk, K., and Sazanov, L.A. (2016) The architecture of respiratory supercomplexes, Nature, 537, 644–648.

40. Rieger, B., Shalaeva, D.N., Sohnel, A.C., Kohl, W., Duwe, P., Mulkidjanian, A.Y., and Busch, K.B. (2017) Lifetime imaging of GFP at CoxVIIIa reports respiratory supercomplex assembly in live cells, Sci. Rep., 7, 46055.

41. Guo, R., Zong, S., Wu, M., Gu, J., and Yang, M. (2017) Architecture of human mitochondrial respiratory megacomplex I2III2IV2, Cell, 170, 1247–1257.

42. Letts, J.A., and Sazanov, L.A. (2017) Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain, Nat. Struct. Mol. Biol., 24, 800–808.

43. Gu, J., Wu, M., Guo, R., Yan, K., Lei, J., Gao, N., and Yang, M. (2016) The architecture of the mammalian respirasome, Nature, 537, 639–643.

44. Sousa, J.S., Mills, D.J., Vonck, J., and Kuhlbrandt, W. (2016) Functional asymmetry and electron flow in the bovine respirasome, Elife, 5, pii: e21290.

45. Haines, T.H. (1983) Anionic lipid headgroups as a proton-conducting pathway along the surface of membranes: a hypothesis, Proc. Natl. Acad. Sci. USA, 80, 160–164.

46. Haines, T.H. (2009) A new look at cardiolipin, Biochim. Biophys. Acta, 1788, 1997–2002.

47. Haines, T.H., and Dencher, N.A. (2002) Cardiolipin: a proton trap for oxidative phosphorylation, FEBS lett., 528, 35–39.

48. Mulkidjanian, A.Y., Heberle, J., and Cherepanov, D.A. (2006) Protons and interfaces: implications for biological energy conversion, Biochim. Biophys. Acta, 1757, 913–930.

49. Mileykovskaya, E., and Dowhan, W. (2000) Visualization of phospholipid domains in Escherichia coli by using the cardiolipin-specific fluorescent dye 10-N-nonyl acridine orange, J. Bacteriol., 182, 1172–1175.

50. Kawai, F., Shoda, M., Harashima, R., Sadaie, Y., Hara, H., and Matsumoto, K. (2004) Cardiolipin domains in Bacillus subtilis marburg membranes, J. Bacteriol., 186, 1475–1483.

51. Weis, R.M., Hirai, T., Chalah, A., Kessel, M., Peters, P.J., and Subramaniam, S. (2003) Electron microscopic analysis of membrane assemblies formed by the bacterial chemotaxis receptor Tsr, J. Bacteriol., 185, 3636–3643.

52. Brookes, P.S., Hulbert, A.J., and Brand, M.D. (1997) The proton permeability of liposomes made from mitochondrial inner membrane phospholipids: no effect of fatty acid composition, Biochim. Biophys. Acta, 1330, 157–164.

53. Shinoda, W. (2016) Permeability across lipid membranes, Biochim. Biophys. Acta, 1858, 2254–2265.

54. Deamer, D.W. (1987) Proton permeation of lipid bilayers, J. Bioenerg. Biomembr., 19, 457–479.

55. Paula, S., Volkov, A.G., Van Hoek, A.N., Haines, T.H., and Deamer, D.W. (1996) Permeation of protons, potassium ions, and small polar molecules through phospholipid bilayers as a function of membrane thickness, Biophys. J., 70, 339–348.

56. Haines, T.H. (2001) Do sterols reduce proton and sodium leaks through lipid bilayers? Prog. Lipid Res., 40, 299–324.

57. Konings, W.N., Albers, S.V., Koning, S., and Driessen, A.J. (2002) The cell membrane plays a crucial role in survival of bacteria and archaea in extreme environments, Antonie Van Leeuwenhoek, 81, 61–72.

58. Mikel’saar, K., Severina, I.I., and Skulachev, V.P. (1974) Phospholipids and oxidative phosphorylation, Usp. Sovrem. Biol., 78, 348–370.

59. Zhang, M., Mileykovskaya, E., and Dowhan, W. (2002) Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane, J. Biol. Chem., 277, 43553–43556.

60. Dibrova, D.V., Cherepanov, D.A., Galperin, M.Y., Skulachev, V.P., and Mulkidjanian, A.Y. (2013) Evolution of cytochrome bc complexes: from membrane-anchored dehydrogenases of ancient bacteria to triggers of apoptosis in vertebrates, Biochim. Biophys. Acta, 1827, 1407–1427.

61. Andreyev, A., Bondareva, T.O., Dedukhova, V.I., Mokhova, E.N., Skulachev, V.P., and Volkov, N.I. (1988) Carboxyatractylate inhibits the uncoupling effect of free fatty acids, FEBS Lett., 226, 265–269.

62. Pebay-Peyroula, E., Dahout-Gonzalez, C., Kahn, R., Trezeguet, V., Lauquin, G.J., and Brandolin, G. (2003) Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside, Nature, 426, 39–44.

63. Ruprecht, J.J., Hellawell, A.M., Harding, M., Crichton, P.G., McCoy, A.J., and Kunji, E.R. (2014) Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism, Proc. Natl. Acad. Sci. USA, 111, E426–434.

64. Nury, H., Dahout-Gonzalez, C., Trezeguet, V., Lauquin, G., Brandolin, G., and Pebay-Peyroula, E. (2005) Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers, FEBS Lett., 579, 6031–6036.

65. Claypool, S.M., Oktay, Y., Boontheung, P., Loo, J.A., and Koehler, C.M. (2008) Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane, J. Cell Biol., 182, 937–950.

66. Lu, Y.W., Acoba, M.G., Selvaraju, K., Huang, T.C., Nirujogi, R.S., Sathe, G., Pandey, A., and Claypool, S.M. (2017) Human adenine nucleotide translocases physically and functionally interact with respirasomes, Mol. Biol. Cell, 28, 1489–1506.

67. Fink, M.P., Macias, C.A., Xiao, J., Tyurina, Y.Y., Jiang, J., Belikova, N., Delude, R.L., Greenberger, J.S., Kagan, V.E., and Wipf, P. (2007) Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted anti-oxidants, Biochem. Pharmacol., 74, 801–809.

68. Birk, A.V., Liu, S., Soong, Y., Mills, W., Singh, P., Warren, J.D., Seshan, S.V., Pardee, J.D., and Szeto, H.H. (2013) The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin, J. Am. Soc. Nephrol., 24, 1250–1261.

69. Szeto, H.H., and Birk, A.V. (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity, Clin. Pharmacol. Ther., 96, 672–683.

70. Kelso, G.F., Porteous, C.M., Coulter, C.V., Hughes, G., Porteous, W.K., Ledgerwood, E.C., Smith, R.A., and Murphy, M.P. (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties, J. Biol. Chem., 276, 4588–4596.

71. Antonenko, Y.N., Avetisyan, A.V., Bakeeva, L.E., Chernyak, B.V., Chertkov, V.A., Domnina, L.V., Ivanova, O.Y., Izyumov, D.S., Khailova, L.S., Klishin, S.S., Korshunova, G.A., Lyamzaev, K.G., Muntyan, M.S., Nepryakhina, O.K., Pashkovskaya, A.A., Pletjushkina, O.Y., Pustovidko, A.V., Roginsky, V.A., Rokitskaya, T.I., Ruuge, E.K., Saprunova, V.B., Severina, I.I, Simonyan, R.A., Skulachev, I.V., Skulachev, M.V., Sumbatyan, N.V., Sviryaeva, I.V., Tashlitsky, V.N., Vassiliev, J.M., Vyssokikh, M.Y., Yaguzhinsky, L.S., Zamyatnin, A.A., Jr., and Skulachev, V.P. (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies, Biochemistry (Moscow), 73, 1273–1287.

72. Severin, F.F., Severina, I.I, Antonenko, Y.N., Rokitskaya, T.I., Cherepanov, D.A., Mokhova, E.N., Vyssokikh, M.Y., Pustovidko, A.V., Markova, O.V., Yaguzhinsky, L.S., Korshunova, G.A., Sumbatyan, N.V., Skulachev, M.V., and Skulachev, V.P. (2010) Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore, Proc. Natl. Acad. Sci. USA, 107, 663–668.

73. Anisimov, V.N., Egorov, M.V., Krasilshchikova, M.S., Lyamzaev, K.G., Manskikh, V.N., Moshkin, M.P., Novikov, E.A., Popovich, I.G., Rogovin, K.A., Shabalina, I.G., Shekarova, O.N., Skulachev, M.V., Titova, T.V., Vygodin, V.A., Vyssokikh, M.Y., Yurova, M.N., Zabezhinsky, M.A., and Skulachev, V.P. (2011) Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents, Aging (Albany N.Y.), 3, 1110–1119.

74. Lyamzaev, K.G., Pustovidko, A.V., Simonyan, R.A., Rokitskaya, T.I., Domnina, L.V., Ivanova, O.Y., Severina, I.I., Sumbatyan, N.V., Korshunova, G.A., Tashlitsky, V.N., Roginsky, V.A., Antonenko, Y.N., Skulachev, M.V., Chernyak, B.V., and Skulachev, V.P. (2011) Novel mitochondria-targeted antioxidants: plastoquinone conjugated with cationic plant alkaloids berberine and palmatine, Pharm. Res., 28, 2883–2895.

75. Skulachev, V.P. (2012) Mitochondria-targeted antioxidants as promising drugs for treatment of age-related brain diseases, J. Alzheimer’s Dis., 28, 283–289.

76. Lokhmatikov, A.V., Voskoboynikova, N.E., Cherepanov, D.A., Sumbatyan, N.V., Korshunova, G.A., Skulachev, M.V., Steinhoff, H.J., Skulachev, V.P., and Mulkidjanian, A.Y. (2014) Prevention of peroxidation of cardiolipin liposomes by quinol-based antioxidants, Biochemistry (Moscow), 79, 1081–1100.

77. Lokhmatikov, A.V., Voskoboynikova, N., Cherepanov, D.A., Skulachev, M.V., Steinhoff, H.J., Skulachev, V.P., and Mulkidjanian, A.Y. (2016) Impact of antioxidants on cardiolipin oxidation in liposomes: why mitochondrial cardiolipin serves as an apoptotic signal? Oxid. Med. Cell Longev., 2016, 8679469.

78. Lenaz, G., and Genova, M.L. (2009) Structural and functional organization of the mitochondrial respiratory chain: a dynamic super-assembly, Int. J. Biochem. Cell Biol., 41, 1750–1772.

79. Hauss, T., Dante, S., Haines, T.H., and Dencher, N.A. (2005) Localization of coenzyme Q10 in the center of a deuterated lipid membrane by neutron diffraction, Biochim. Biophys. Acta, 1710, 57–62.

80. Xu, Y., Phoon, C.K., Berno, B., D’Souza, K., Hoedt, E., Zhang, G., Neubert, T.A., Epand, R.M., Ren, M., and Schlame, M. (2016) Loss of protein association causes cardiolipin degradation in Barth syndrome, Nat. Chem. Biol., 12, 641–647.

81. Amchenkova, A.A., Bakeeva, L.E., Chentsov, Y.S., Skulachev, V.P., and Zorov, D.B. (1988) Coupling membranes as energy-transmitting cables. I. Filamentous mitochondria in fibroblasts and mitochondrial clusters in cardiomyocytes, J. Cell Biol., 107, 481–495.

82. Skulachev, V.P., Bakeeva, L.E., Chernyak, B.V., Domnina, L.V., Minin, A.A., Pletjushkina, O.Y., Saprunova, V.B., Skulachev, I.V., Tsyplenkova, V.G., Vasiliev, J.M., Yaguzhinsky, L.S., and Zorov, D.B. (2004) Thread-grain transition of mitochondrial reticulum as a step of mitoptosis and apoptosis, Mol. Cell Biochem., 256–257, 341–358.

83. Fenton, H.J.H. (1876) On a new reaction of tartaric acid, Chem. News, 33.

84. Dunford, H.B. (2002) Oxidations of iron(II)/(III) by hydrogen peroxide: from aquo to enzyme, Coordin. Chem. Rev., 233, 311–318.

85. Barbusinski, K. (2009) Fenton reaction – controversy concerning the chemistry, Ecol. Chem. Eng. S, 16, 347–358.

86. Lill, R., Srinivasan, V., and Muhlenhoff, U. (2014) The role of mitochondria in cytosolic-nuclear iron-sulfur protein biogenesis and in cellular iron regulation, Curr. Opin. Microbiol., 22, 111–119.

87. Porter, N.A., Caldwell, S.E., and Mills, K.A. (1995) Mechanisms of free radical oxidation of unsaturated lipids, Lipids, 30, 277–290.

88. Echtay, K.S., Roussel, D., St-Pierre, J., Jekabsons, M.B., Cadenas, S., Stuart, J.A., Harper, J.A., Roebuck, S.J., Morrison, A., Pickering, S., Clapham, J.C., and Brand, M.D. (2002) Superoxide activates mitochondrial uncoupling proteins, Nature, 415, 96–99.

89. Divakaruni, A.S., and Brand, M.D. (2011) The regulation and physiology of mitochondrial proton leak, Physiology (Bethesda), 26, 192–205.

90. Jastroch, M., Divakaruni, A.S., Mookerjee, S., Treberg, J.R., and Brand, M.D. (2010) Mitochondrial proton and electron leaks, Essays Biochem., 47, 53–67.

91. Starkov, A.A. (2006) Protein-mediated energy-dissipating pathways in mitochondria, Chem. Biol. Interact., 163, 133–144.

92. Firsov, A.M., Kotova, E.A., Korepanova, E.A., Osipov, A.N., and Antonenko, Y.N. (2015) Peroxidative permeabilization of liposomes induced by cytochrome c/cardiolipin complex, Biochim. Biophys. Acta, 1848, 767–774.

93. Brookes, P.S. (2005) Mitochondrial H(+) leak and ROS generation: an odd couple, Free Radic. Biol. Med., 38, 12–23.

94. Cheng, J., Nanayakkara, G., Shao, Y., Cueto, R., Wang, L., Yang, W.Y., Tian, Y., Wang, H., and Yang, X. (2017) Mitochondrial proton leak plays a critical role in pathogenesis of cardiovascular diseases, Adv. Exp. Med. Biol., 982, 359–370.

95. Petrosillo, G., Casanova, G., Matera, M., Ruggiero, F.M., and Paradies, G. (2006) Interaction of peroxidized cardiolipin with rat-heart mitochondrial membranes: induction of permeability transition and cytochrome c release, FEBS Lett., 580, 6311–6316.

96. Skulachev, V.P. (1999) Anion carriers in fatty acid-mediated physiological uncoupling, J. Bioenerg. Biomembr., 31, 431–445.

97. Nicholls, D.G. (2004) Mitochondrial membrane potential and aging, Aging Cell, 3, 35–40.

98. Azzu, V., Jastroch, M., Divakaruni, A.S., and Brand, M.D. (2010) The regulation and turnover of mitochondrial uncoupling proteins, Biochim. Biophys. Acta, 1797, 785–791.

99. Berardi, M.J., Shih, W.M., Harrison, S.C., and Chou, J.J. (2011) Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching, Nature, 476, 109–113.

100. Skulachev, V.P. (1991) Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation, FEBS Lett., 294, 158–162.

101. Garlid, K.D. (1996) Cation transport in mitochondria – the potassium cycle, Biochim. Biophys. Acta, 1275, 123–126.

102. Berardi, M.J., and Chou, J.J. (2014) Fatty acid flippase activity of UCP2 is essential for its proton transport in mitochondria, Cell Metab., 20, 541–552.

103. Fedorenko, A., Lishko, P.V., and Kirichok, Y. (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria, Cell, 151, 400–413.

104. Schonfeld, P., Schild, L., and Kunz, W. (1989) Long-chain fatty acids act as protonophoric uncouplers of oxidative phosphorylation in rat liver mitochondria, Biochim. Biophys. Acta, 977, 266–272.

105. Perez, C., Gerber, S., Boilevin, J., Bucher, M., Darbre, T., Aebi, M., Reymond, J.L., and Locher, K.P. (2015) Structure and mechanism of an active lipid-linked oligosaccharide flippase, Nature, 524, 433–438.

106. Andreyev, A., Bondareva, T.O., Dedukhova, V.I., Mokhova, E.N., Skulachev, V.P., Tsofina, L.M., Volkov, N.I., and Vygodina, T.V. (1989) The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria, Eur. J. Biochem., 182, 585–592.

107. Lee, Y., Willers, C., Kunji, E.R., and Crichton, P.G. (2015) Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin, Proc. Natl. Acad. Sci. USA, 112, 6973–6978.

108. Chouchani, E.T., Kazak, L., Jedrychowski, M.P., Lu, G.Z., Erickson, B.K., Szpyt, J., Pierce, K.A., Laznik-Bogoslavski, D., Vetrivelan, R., Clish, C.B., Robinson, A.J., Gygi, S.P., and Spiegelman, B.M. (2016) Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1, Nature, 532, 112–116.

109. Lo Conte, M., and Carroll, K.S. (2013) The redox biochemistry of protein sulfenylation and sulfinylation, J. Biol. Chem., 288, 26480–26488.

110. Little, C., and O’Brien, P.J. (1968) The effectiveness of a lipid peroxide in oxidizing protein and non-protein thiols, Biochem. J., 106, 419–423.

111. Korshunov, S.S., Skulachev, V.P., and Starkov, A.A. (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria, FEBS Lett., 416, 15–18.

112. Pletjushkina, O.Y., Lyamzaev, K.G., Popova, E.N., Nepryakhina, O.K., Ivanova, O.Y., Domnina, L.V., Chernyak, B.V., and Skulachev, V.P. (2006) Effect of oxidative stress on dynamics of mitochondrial reticulum, Biochim. Biophys. Acta, 1757, 518–524.

113. Iqbal, S., and Hood, D.A. (2014) Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts, Am. J. Physiol. Cell Physiol., 306, C1176–1183.

114. Willems, P.H., Rossignol, R., Dieteren, C.E., Murphy, M.P., and Koopman, W.J. (2015) Redox homeostasis and mitochondrial dynamics, Cell Metab., 22, 207–218.

115. Vorobjev, I.A., and Zorov, D.B. (1983) Diazepam inhibits cell respiration and induces fragmentation of mitochondrial reticulum, FEBS Lett., 163, 311–314.

116. Zorov, D.B., Filburn, C.R., Klotz, L.O., Zweier, J.L., and Sollott, S.J. (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes, J. Exp. Med., 192, 1001–1014.

117. Zorov, D.B., Juhaszova, M., and Sollott, S.J. (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release, Physiol. Rev., 94, 909–950.

118. Frank, S., Gaume, B., Bergmann-Leitner, E.S., Leitner, W.W., Robert, E.G., Catez, F., Smith, C.L., and Youle, R.J. (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis, Dev. Cell, 1, 515–525.

119. Jones, E., Gaytan, N., Garcia, I., Herrera, A., Ramos, M., Agarwala, D., Rana, M., Innis-Whitehouse, W., Schuenzel, E., and Gilkerson, R. (2017) A threshold of transmembrane potential is required for mitochondrial dynamic balance mediated by DRP1 and OMA1, Cell. Mol. Life Sci., 74, 1347–1363.

120. Baker, M.J., Lampe, P.A., Stojanovski, D., Korwitz, A., Anand, R., Tatsuta, T., and Langer, T. (2014) Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics, EMBO J., 33, 578–593.

121. MacVicar, T., and Langer, T. (2016) OPA1 processing in cell death and disease – the long and short of it, J. Cell Sci., 129, 2297–2306.

122. Jiang, X., and Wang, X. (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1, J. Biol. Chem., 275, 31199–31203.

123. Riedl, S.J., and Salvesen, G.S. (2007) The apoptosome: signalling platform of cell death, Nat. Rev. Mol. Cell Biol., 8, 405–413.

124. Brustugun, O.T., Fladmark, K.E., Doskeland, S.O., Orrenius, S., and Zhivotovsky, B. (1998) Apoptosis induced by microinjection of cytochrome c is caspase-dependent and is inhibited by Bcl-2, Cell Death Differ., 5, 660–668.

125. Bogenhagen, D., and Clayton, D.A. (1974) The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells. Quantitative isolation of mitochondrial deoxyribonucleic acid, J. Biol. Chem., 249, 7991–7995.

126. Stowe, D.F., and Camara, A.K. (2009) Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function, Antioxid. Redox Signal., 11, 1373–1414.

127. Goldstein, J.C., Waterhouse, N.J., Juin, P., Evan, G.I., and Green, D.R. (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant, Nat. Cell Biol., 2, 156–162.

128. Renault, T.T., Floros, K.V., Elkholi, R., Corrigan, K.A., Kushnareva, Y., Wieder, S.Y., Lindtner, C., Serasinghe, M.N., Asciolla, J.J., Buettner, C., Newmeyer, D.D., and Chipuk, J.E. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis, Mol. Cell, 57, 69–82.

129. Szabadkai, G., Simoni, A.M., Chami, M., Wieckowski, M.R., Youle, R.J., and Rizzuto, R. (2004) Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis, Mol. Cell, 16, 59–68.

130. Perfettini, J.L., Roumier, T., and Kroemer, G. (2005) Mitochondrial fusion and fission in the control of apoptosis, Trends Cell Biol., 15, 179–183.

131. Brookes, P.S., Yoon, Y., Robotham, J.L., Anders, M.W., and Sheu, S.S. (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle, Am. J. Physiol. Cell Physiol., 287, C817–833.

132. Ott, M., Gogvadze, V., Orrenius, S., and Zhivotovsky, B. (2007) Mitochondria, oxidative stress and cell death, Apoptosis, 12, 913–922.

133. Green, D.R., Galluzzi, L., and Kroemer, G. (2014) Cell biology. Metabolic control of cell death, Science, 345, 1250256.

134. Narendra, D.P., Jin, S.M., Tanaka, A., Suen, D.F., Gautier, C.A., Shen, J., Cookson, M.R., and Youle, R.J. (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin, PLoS Biol., 8, e1000298.

135. Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C.A., Sou, Y.S., Saiki, S., Kawajiri, S., Sato, F., Kimura, M., Komatsu, M., Hattori, N., and Tanaka, K. (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy, J. Cell Biol., 189, 211–221.

136. Chu, C.T., Ji, J., Dagda, R.K., Jiang, J.F., Tyurina, Y.Y., Kapralov, A.A., Tyurin, V.A., Yanamala, N., Shrivastava, I.H., Mohammadyani, D., Wang, K.Z.Q., Zhu, J., Klein-Seetharaman, J., Balasubramanian, K., Amoscato, A.A., Borisenko, G., Huang, Z., Gusdon, A.M., Cheikhi, A., Steer, E.K., Wang, R., Baty, C., Watkins, S., Bahar, I., Bayir, H., and Kagan, V.E. (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells, Nat. Cell Biol., 15, 1197–1205.

137. Novak, I., Kirkin, V., McEwan, D.G., Zhang, J., Wild, P., Rozenknop, A., Rogov, V., Lohr, F., Popovic, D., Occhipinti, A., Reichert, A.S., Terzic, J., Dotsch, V., Ney, P.A., and Dikic, I. (2010) Nix is a selective autophagy receptor for mitochondrial clearance, EMBO Rep., 11, 45–51.

138. Kagan, V.E., Jiang, J., Huang, Z., Tyurina, Y.Y., Desbourdes, C., Cottet-Rousselle, C., Dar, H.H., Verma, M., Tyurin, V.A., Kapralov, A.A., Cheikhi, A., Mao, G., Stolz, D., St. Croix, C.M., Watkins, S., Shen, Z., Li, Y., Greenberg, M.L., Tokarska-Schlattner, M., Boissan, M., Lacombe, M.L., Epand, R.M., Chu, C.T., Mallampalli, R.K., Bayir, H., and Schlattner, U. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy, Cell Death Differ., 23, 1140–1151.

139. Quiros, P.M., Langer, T., and Lopez-Otin, C. (2015) New roles for mitochondrial proteases in health, ageing and disease, Nat. Rev. Mol. Cell Biol., 16, 345–359.

140. Burman, J.L., Pickles, S., Wang, C., Sekine, S., Vargas, J.N.S., Zhang, Z., Youle, A.M., Nezich, C.L., Wu, X., Hammer, J.A., and Youle, R.J. (2017) Mitochondrial fission facilitates the selective mitophagy of protein aggregates, J. Cell Biol., 216, 3231–3247.

141. Frank, M., Duvezin-Caubet, S., Koob, S., Occhipinti, A., Jagasia, R., Petcherski, A., Ruonala, M.O., Priault, M., Salin, B., and Reichert, A.S. (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner, Biochim. Biophys. Acta, 1823, 2297–2310.

142. Levraut, J., Iwase, H., Shao, Z.H., Vanden Hoek, T.L., and Schumacker, P.T. (2003) Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation, Am. J. Physiol. Heart Circ. Physiol., 284, H549–558.

143. Fan, X., Hussien, R., and Brooks, G.A. (2010) H2O2-induced mitochondrial fragmentation in C2C12 myocytes, Free Radic. Biol. Med., 49, 1646–1654.

144. Arimura, S.I., Kurisu, R., Sugaya, H., Kadoya, N., and Tsutsumi, N. (2017) Cold treatment induces transient mitochondrial fragmentation in Arabidopsis thaliana in a way that requires DRP3A but not ELM1 or an ELM1-like homologue, ELM2, Int. J. Mol. Sci., 18, e2161.

145. Rosdah, A.A., J, K.H., Delbridge, L.M., Dusting, G.J., and Lim, S.Y. (2016) Mitochondrial fission – a drug target for cytoprotection or cytodestruction? Pharmacol. Res. Perspect., 4, e00235.

146. Karbowski, M., Arnoult, D., Chen, H., Chan, D.C., Smith, C.L., and Youle, R.J. (2004) Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis, J. Cell Biol., 164, 493–499.

147. Karbowski, M., and Youle, R.J. (2003) Dynamics of mitochondrial morphology in healthy cells and during apoptosis, Cell Death Differ., 10, 870–880.

148. Kagan, V.E., Bayir, H.A., Belikova, N.A., Kapralov, O., Tyurina, Y.Y., Tyurin, V.A., Jiang, J., Stoyanovsky, D.A., Wipf, P., Kochanek, P.M., Greenberger, J.S., Pitt, B., Shvedova, A.A., and Borisenko, G. (2009) Cytochrome c/ cardiolipin relations in mitochondria: a kiss of death, Free Radic. Biol. Med., 46, 1439–1453.

149. Jezek, P., Zackova, M., Ruzicka, M., Skobisova, E., and Jaburek, M. (2004) Mitochondrial uncoupling proteins – facts and fantasies, Physiol. Res., 53, S199–211.

150. Crichton, P.G., Lee, Y., and Kunji, E.R. (2017) The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism, Biochimie, 134, 35–50.