Calcium Transport Systems in Mitochondria: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Lily Guo and Version 2 by Nataliia Naumova.

Calcium (Ca2+) is a divalent cation and a universal second messenger that regulates the most important functions and facets of all eukaryotic cells, including: gene expression, proliferation, regulation of bioenergetics, contraction of muscles, mediation of fertilization, and many other cellular functions [1–5]. Regulation of free intracellular concentration of Ca2+ is an important mechanism for intracellular signaling, and it is a key component in the mediation of many cell functions and biochemical reactions, being crucial for signal transduction in cells [2,6–10]. On top of all that, intra-mitochondrial Ca2+ regulates a cascade of physiological and pathophysiological processes in cells [10–15]. The normal level of intra-mitochondrial Са2+ is essential for the correct functioning of mitochondria; whereas Ca2+ overload is typical for a wide range of mitochondrial dysfunctions and pathophysiological processes [14,15,37,39,41]. Homeostasis of Ca2+ in the mitochondria is determined by the delicate balance of mitochondrial Ca2+ transport systems in both the inner (IMM) and outer mitochondrial membrane (OMM). Ca2+ influx and efflux systems are composed of different components, including: channels, pumps, antiporters, or Ca2+ binding proteins that cooperate to maintain intra-mitochondrial Ca2+ homeostasis [10,14,38,39,42].

Calcium (Ca2+) is a divalent cation and a universal second messenger that regulates the most important functions and facets of all eukaryotic cells, including: gene expression, proliferation, regulation of bioenergetics, contraction of muscles, mediation of fertilization, and many other cellular functions. Regulation of free intracellular concentration of Ca2+ is an important mechanism for intracellular signaling, and it is a key component in the mediation of many cell functions and biochemical reactions, being crucial for signal transduction in cells. On top of all that, intra-mitochondrial Ca2+ regulates a cascade of physiological and pathophysiological processes in cells The normal level of intra-mitochondrial Са2+ is essential for the correct functioning of mitochondria; whereas Ca2+ overload is typical for a wide range of mitochondrial dysfunctions and pathophysiological processes. Homeostasis of Ca2+ in the mitochondria is determined by the delicate balance of mitochondrial Ca2+ transport systems in both the inner (IMM) and outer mitochondrial membrane (OMM). Ca2+ influx and efflux systems are composed of different components, including: channels, pumps, antiporters, or Ca2+ binding proteins that cooperate to maintain intra-mitochondrial Ca2+ homeostasis.

  • mitochondria
  • Calcium transport
  • VDAC
  • MCU
  • RaM
  • mRyR
  • mPTP
  • LETM1
  • NCLX
  • HCX
Please wait, diff process is still running!

References

  1. Carafoli, E.; Krebs, J. Why Calcium? How Calcium Became the Best Communicator. J. Biol. Chem. 2016, 291, 20849–20857, doi:10.1074/jbc.R116.735894.
  2. Membrane Dynamics and Calcium Signaling; Krebs, J., Ed.; Advances in Experimental Medicine and Biology; Springer International Publishing: Cham, 2017; Vol. 981; ISBN 978-3-319-55857-8.
  3. Del Re, D.P.; Amgalan, D.; Linkermann, A.; Liu, Q.; Kitsis, R.N. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol. Rev. 2019, 99, 1765–1817, doi:10.1152/physrev.00022.2018.
  4. Eisner, D.A.; Caldwell, J.L.; Kistamás, K.; Trafford, A.W. Calcium and Excitation-Contraction Coupling in the Heart. Circ. Res. 2017, 121, 181–195, doi:10.1161/CIRCRESAHA.117.310230.
  5. Brini, M.; Calì, T.; Ottolini, D.; Carafoli, E. Neuronal calcium signaling: function and dysfunction. Cell. Mol. Life Sci. 2014, 71, 2787–2814, doi:10.1007/s00018-013-1550-7.
  6. Duchen, M.R. Ca2+-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem. J. 1992, 283, 41–50, doi:10.1042/bj2830041.
  7. Elustondo, P.A.; Nichols, M.; Robertson, G.S.; Pavlov, E. V Mitochondrial Ca2+ uptake pathways. J. Bioenerg. Biomembr. 2017, 49, 113—119, doi:10.1007/s10863-016-9676-6.
  8. Duchen, M.R. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol. Aspects Med. 2004, 25, 365–451, doi:10.1016/j.mam.2004.03.001.
  9. Mitochondrial Dynamics in Cardiovascular Medicine; Santulli, G., Ed.; Advances in Experimental Medicine and Biology; Springer International Publishing: Cham, 2017; Vol. 982; ISBN 978-3-319-55329-0.
  10. Bravo-Sagua, R.; Parra, V.; Lopez-Crisosto, C.; Diaz, P.; Quest, A.F.G.; Lavandero, S. Calcium Transport and Signaling in Mitochondria. Compr. Physiol. 2017, 7, 623–634, doi:10.1002/cphy.c160013.
  11. Giorgio, V.; Guo, L.; Bassot, C.; Petronilli, V.; Bernardi, P. Calcium and regulation of the mitochondrial permeability transition. Cell Calcium 2018, 70, 56–63, doi:10.1016/j.ceca.2017.05.004.
  12. Delierneux, C.; Kouba, S.; Shanmughapriya, S.; Potier-Cartereau, M.; Trebak, M.; Hempel, N. Mitochondrial Calcium Regulation of Redox Signaling in Cancer. Cells 2020, 9, doi:10.3390/cells9020432.
  13. Belosludtsev, K.N.; Dubinin, M. V; Belosludtseva, N. V; Mironova, G.D. Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochemistry. (Mosc). 2019, 84, 593–607, doi:10.1134/S0006297919060026.
  14. Hausenloy, D.J.; Schulz, R.; Girao, H.; Kwak, B.R.; De Stefani, D.; Rizzuto, R.; Bernardi, P.; Di Lisa, F. Mitochondrial ion channels as targets for cardioprotection. J. Cell. Mol. Med. 2020, 24, 7102–7114, doi:10.1111/jcmm.15341.
  15. Glaser, T.; Arnaud Sampaio, V.F.; Lameu, C.; Ulrich, H. Calcium signalling: A common target in neurological disorders and neurogenesis. Semin. Cell Dev. Biol. 2019, 95, 25–33, doi:10.1016/j.semcdb.2018.12.002.
  16. McCarron, J.G.; Saunter, C.; Wilson, C.; Girkin, J.M.; Chalmers, S. Mitochondria Structure and Position in the Local Control of Calcium Signals in Smooth Muscle Cells; CRC Press, 2018; ISBN 9781498774222.
  17. Bock, F.J.; Tait, S.W.G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 2020, 21, 85–100, doi:10.1038/s41580-019-0173-8.
  18. Wacquier, B.; Combettes, L.; Dupont, G. Dual dynamics of mitochondrial permeability transition pore opening. Sci. Rep. 2020, 10, 3924, doi:10.1038/s41598-020-60177-1.
  19. Denton, R.M. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta - Bioenerg. 2009, 1787, 1309–1316, doi:10.1016/j.bbabio.2009.01.005.
  20. Picard, M.; Wallace, D.C.; Burelle, Y. The rise of mitochondria in medicine. Mitochondrion 2016, 30, 105–116, doi:10.1016/j.mito.2016.07.003.
  21. Duchen, M.R. Mitochondria and calcium: from cell signalling to cell death. J. Physiol. 2000, 529, 57–68, doi:10.1111/j.1469-7793.2000.00057.x.
  22. Park, M.K. Perinuclear, perigranular and sub-plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J. 2001, 20, 1863–1874, doi:10.1093/emboj/20.8.1863.
  23. Giorgi, C.; Marchi, S.; Pinton, P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat. Rev. Mol. Cell Biol. 2018, 19, 713–730, doi:10.1038/s41580-018-0052-8.
  24. Giacomello, M.; Pyakurel, A.; Glytsou, C.; Scorrano, L. The cell biology of mitochondrial membrane dynamics. Nat. Rev. Mol. Cell Biol. 2020, 21, 204–224, doi:10.1038/s41580-020-0210-7.
  25. Morciano, G.; Marchi, S.; Morganti, C.; Sbano, L.; Bittremieux, M.; Kerkhofs, M.; Corricelli, M.; Danese, A.; Karkucinska-Wieckowska, A.; Wieckowski, M.R.; et al. Role of Mitochondria-Associated ER Membranes in Calcium Regulation in Cancer-Specific Settings. Neoplasia 2018, 20, 510–523, doi:10.1016/j.neo.2018.03.005.
  26. Herrera-Cruz, M.S.; Simmen, T. Cancer: Untethering Mitochondria from the Endoplasmic Reticulum? Front. Oncol. 2017, 7, doi:10.3389/fonc.2017.00105.
  27. Singaravelu, K.; Nelson, C.; Bakowski, D.; de Brito, O.M.; Ng, S.-W.; Di Capite, J.; Powell, T.; Scorrano, L.; Parekh, A.B. Mitofusin 2 Regulates STIM1 Migration from the Ca 2+ Store to the Plasma Membrane in Cells with Depolarized Mitochondria. J. Biol. Chem. 2011, 286, 12189–12201, doi:10.1074/jbc.M110.174029.
  28. Jouaville, L.S.; Pinton, P.; Bastianutto, C.; Rutter, G.A.; Rizzuto, R. Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming. Proc. Natl. Acad. Sci. 1999, 96, 13807–13812, doi:10.1073/pnas.96.24.13807.
  29. Carpio, M.A.; Katz, S.G. Methods to Probe Calcium Regulation by BCL-2 Family Members. Methods Mol. Biol. 2019, 1877, 173–183, doi:10.1007/978-1-4939-8861-7_12.
  30. Rong, Y.; Distelhorst, C.W. Bcl-2 Protein Family Members: Versatile Regulators of Calcium Signaling in Cell Survival and Apoptosis. Annu. Rev. Physiol. 2008, 70, 73–91, doi:10.1146/annurev.physiol.70.021507.105852.
  31. Briston, T.; Roberts, M.; Lewis, S.; Powney, B.; M. Staddon, J.; Szabadkai, G.; Duchen, M.R. Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate availability. Sci. Rep. 2017, 7, 10492, doi:10.1038/s41598-017-10673-8.
  32. Bonora, M.; Patergnani, S.; Ramaccini, D.; Morciano, G.; Pedriali, G.; Kahsay, A.E.; Bouhamida, E.; Giorgi, C.; Wieckowski, M.R.; Pinton, P. Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology. Biomolecules 2020, 10, 998, doi:10.3390/biom10070998.
  33. VASINGTON, F.D.; MURPHY, J. V Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J. Biol. Chem. 1962, 237, 2670–2677.
  34. DeLuca, H.F.; Engstrom, G.W. CALCIUM UPTAKE BY RAT KIDNEY MITOCHONDRIA. Proc. Natl. Acad. Sci. 1961, 47, 1744–1750, doi:10.1073/pnas.47.11.1744.
  35. MITCHELL, P.; MOYLE, J. Chemiosmotic Hypothesis of Oxidative Phosphorylation. Nature 1967, 213, 137–139, doi:10.1038/213137a0.
  36. Ludtmann, M.H.R.; Abramov, A.Y. Mitochondrial calcium imbalance in Parkinson’s disease. Neurosci. Lett. 2018, 663, 86–90, doi:10.1016/j.neulet.2017.08.044.
  37. Bhosale, G.; Sharpe, J.A.; Sundier, S.Y.; Duchen, M.R. Calcium signaling as a mediator of cell energy demand and a trigger to cell death. Ann. N. Y. Acad. Sci. 2015, 1350, 107–116, doi:10.1111/nyas.12885.
  38. Rossi, A.; Pizzo, P.; Filadi, R. Calcium, mitochondria and cell metabolism: A functional triangle in bioenergetics. Biochim. Biophys. acta. Mol. cell Res. 2019, 1866, 1068–1078, doi:10.1016/j.bbamcr.2018.10.016.
  39. Bertero, E.; Maack, C. Calcium Signaling and Reactive Oxygen Species in Mitochondria. Circ. Res. 2018, 122, 1460–1478, doi:10.1161/CIRCRESAHA.118.310082.
  40. Missiroli, S.; Perrone, M.; Genovese, I.; Pinton, P.; Giorgi, C. Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours. EBioMedicine 2020, 59, 102943, doi:10.1016/j.ebiom.2020.102943.
  41. Burgoyne, J.R.; Mongue-Din, H.; Eaton, P.; Shah, A.M. Redox Signaling in Cardiac Physiology and Pathology. Circ. Res. 2012, 111, 1091–1106, doi:10.1161/CIRCRESAHA.111.255216.
  42. Mammucari, C.; Raffaello, A.; Vecellio Reane, D.; Gherardi, G.; De Mario, A.; Rizzuto, R. Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models. Pflugers Arch. 2018, 470, 1165–1179, doi:10.1007/s00424-018-2123-2.
  43. Ben-Hail, D.; Shoshan-Barmatz, V. VDAC1-interacting anion transport inhibitors inhibit VDAC1 oligomerization and apoptosis. Biochim. Biophys. Acta - Mol. Cell Res. 2016, 1863, 1612–1623, doi:10.1016/j.bbamcr.2016.04.002.
  44. Schein, S.J.; Colombini, M.; Finkelstein, A. Reconstitution in planar lipid bilayers of a voltage-dependent anion-selective channel obtained from paramecium mitochondria. J. Membr. Biol. 1976, 30, 99–120, doi:10.1007/bf01869662.
  45. Mazure, N.M. VDAC in cancer. Biochim. Biophys. Acta - Bioenerg. 2017, 1858, 665–673, doi:10.1016/j.bbabio.2017.03.002.
  46. Becker, T.; Wagner, R. Mitochondrial Outer Membrane Channels: Emerging Diversity in Transport Processes. BioEssays 2018, 40, 1800013, doi:10.1002/bies.201800013.
  47. Rostovtseva, T.K.; Queralt-Martín, M.; Rosencrans, W.M.; Bezrukov, S.M. Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs. Front. Physiol. 2020, 11, 446, doi:10.3389/fphys.2020.00446.
  48. Shoshan-Barmatz, V.; Gincel, D. The voltage-dependent anion channel: characterization, modulation, and role in mitochondrial function in cell life and death. Cell Biochem. Biophys. 2003, 39, 279–292, doi:10.1385/CBB:39:3:279.
  49. Colombini, M.; Mannella, C.A. VDAC, The early days. Biochim. Biophys. Acta - Biomembr. 2012, 1818, 1438–1443, doi:10.1016/j.bbamem.2011.11.014.
  50. COLOMBINI, M. A candidate for the permeability pathway of the outer mitochondrial membrane. Nature 1979, 279, 643–645, doi:10.1038/279643a0.
  51. Kusano, T.; Tateda, C.; Berberich, T.; Takahashi, Y. Voltage-dependent anion channels: their roles in plant defense and cell death. Plant Cell Rep. 2009, 28, 1301–1308, doi:10.1007/s00299-009-0741-z.
  52. Shoshan-Barmatz, V.; Mizrachi, D. VDAC1: from structure to cancer therapy. Front. Oncol. 2012, 2, 164, doi:10.3389/fonc.2012.00164.
  53. Camara, A.K.S.; Zhou, Y.; Wen, P.-C.; Tajkhorshid, E.; Kwok, W.-M. Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target. Front. Physiol. 2017, 8, doi:10.3389/fphys.2017.00460.
  54. Ponnalagu, D.; Singh, H. Anion Channels of Mitochondria. In Handbook of experimental pharmacology; Germany, 2016; Vol. 240, pp. 71–101.
  55. Neumann, D.; Bückers, J.; Kastrup, L.; Hell, S.W.; Jakobs, S. Two-color STED microscopy reveals different degrees of colocalization between hexokinase-I and the three human VDAC isoforms. PMC Biophys. 2010, 3, 4, doi:10.1186/1757-5036-3-4.
  56. Geula, S.; Ben-Hail, D.; Shoshan-Barmatz, V. Structure-based analysis of VDAC1: N-terminus location, translocation, channel gating and association with anti-apoptotic proteins. Biochem. J. 2012, 444, 475–485, doi:10.1042/BJ20112079.
  57. Cheng, E.H.Y.; Sheiko, T. V; Fisher, J.K.; Craigen, W.J.; Korsmeyer, S.J. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 2003, 301, 513–517, doi:10.1126/science.1083995.
  58. Checchetto, V.; Reina, S.; Magrì, A.; Szabo, I.; De Pinto, V. Recombinant Human Voltage Dependent Anion Selective Channel Isoform 3 (hVDAC3) Forms Pores with a Very Small Conductance. Cell. Physiol. Biochem. 2014, 34, 842–853, doi:10.1159/000363047.
  59. De Pinto, V.; Guarino, F.; Guarnera, A.; Messina, A.; Reina, S.; Tomasello, F.M.; Palermo, V.; Mazzoni, C. Characterization of human VDAC isoforms: a peculiar function for VDAC3? Biochim. Biophys. Acta 2010, 1797, 1268—1275, doi:10.1016/j.bbabio.2010.01.031.
  60. Lemasters, J.J.; Holmuhamedov, E.L.; Czerny, C.; Zhong, Z.; Maldonado, E.N. Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect. Biochim. Biophys. Acta 2012, 1818, 1536—1544, doi:10.1016/j.bbamem.2011.11.034.
  61. Austin, S.; Nowikovsky, K. LETM1: Essential for Mitochondrial Biology and Cation Homeostasis? Trends Biochem. Sci. 2019, 44, 648–658, doi:10.1016/j.tibs.2019.04.002.
  62. Li, Y.; Tran, Q.; Shrestha, R.; Piao, L.; Park, S.; Park, J.; Park, J. LETM1 is required for mitochondrial homeostasis and cellular viability (Review). Mol. Med. Rep. 2019, 19, 3367–3375, doi:10.3892/mmr.2019.10041.
  63. Shao, J.; Fu, Z.; Ji, Y.; Guan, X.; Guo, S.; Ding, Z.; Yang, X.; Cong, Y.; Shen, Y. Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca(2+)/H(+) antiporter. Sci. Rep. 2016, 6, 34174, doi:10.1038/srep34174.
  64. Waldeck-Weiermair, M.; Jean-Quartier, C.; Rost, R.; Khan, M.J.; Vishnu, N.; Bondarenko, A.I.; Imamura, H.; Malli, R.; Graier, W.F. Leucine Zipper EF Hand-containing Transmembrane Protein 1 (Letm1) and Uncoupling Proteins 2 and 3 (UCP2/3) Contribute to Two Distinct Mitochondrial Ca 2+ Uptake Pathways. J. Biol. Chem. 2011, 286, 28444–28455, doi:10.1074/jbc.M111.244517.
  65. De Stefani, D.; Raffaello, A.; Teardo, E.; Szabo, I.; Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 2011, 476, 336–340, doi:10.1038/nature10230.
  66. Baughman, J.M.; Perocchi, F.; Girgis, H.S.; Plovanich, M.; Belcher-Timme, C.A.; Sancak, Y.; Bao, X.R.; Strittmatter, L.; Goldberger, O.; Bogorad, R.L.; et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 2011, 476, 341–345, doi:10.1038/nature10234.
  67. Gunter, T.E.; Pfeiffer, D.R. Mechanisms by which mitochondria transport calcium. Am. J. Physiol. 1990, 258, C755-86, doi:10.1152/ajpcell.1990.258.5.C755.
  68. Mishra, J.; Jhun, B.S.; Hurst, S.; O-Uchi, J.; Csordás, G.; Sheu, S.-S. The Mitochondrial Ca2+ Uniporter: Structure, Function, and Pharmacology. Handb. Exp. Pharmacol. 2017, 240, 129—156, doi:10.1007/164_2017_1.
  69. Pallafacchina, G.; Zanin, S.; Rizzuto, R. Recent advances in the molecular mechanism of mitochondrial calcium uptake. F1000Research 2018, 7, 1858, doi:10.12688/f1000research.15723.1.
  70. Granatiero, V.; De Stefani, D.; Rizzuto, R. Mitochondrial Calcium Handling in Physiology and Disease. Adv. Exp. Med. Biol. 2017, 982, 25–47, doi:10.1007/978-3-319-55330-6_2.
  71. Sancak, Y.; Markhard, A.L.; Kitami, T.; Kovacs-Bogdan, E.; Kamer, K.J.; Udeshi, N.D.; Carr, S.A.; Chaudhuri, D.; Clapham, D.E.; Li, A.A.; et al. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 2013, 342, 1379–1382, doi:10.1126/science.1242993.
  72. Cui, C.; Yang, J.; Fu, L.; Wang, M.; Wang, X. Progress in understanding mitochondrial calcium uniporter complex‐mediated calcium signalling: A potential target for cancer treatment. Br. J. Pharmacol. 2019, 176, 1190–1205, doi:10.1111/bph.14632.
  73. Pathak, T.; Trebak, M. Mitochondrial Ca2+ signaling. Pharmacol. Ther. 2018, 192, 112–123, doi:10.1016/j.pharmthera.2018.07.001.
  74. Raffaello, A.; De Stefani, D.; Sabbadin, D.; Teardo, E.; Merli, G.; Picard, A.; Checchetto, V.; Moro, S.; Szabo, I.; Rizzuto, R. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J. 2013, 32, 2362–2376, doi:10.1038/emboj.2013.157.
  75. Patron, M.; Checchetto, V.; Raffaello, A.; Teardo, E.; Vecellio Reane, D.; Mantoan, M.; Granatiero, V.; Szabo, I.; De Stefani, D.; Rizzuto, R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 2014, 53, 726–737, doi:10.1016/j.molcel.2014.01.013.
  76. Csordás, G.; Golenár, T.; Seifert, E.L.; Kamer, K.J.; Sancak, Y.; Perocchi, F.; Moffat, C.; Weaver, D.; de la Fuente Perez, S.; Bogorad, R.; et al. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab. 2013, 17, 976—987, doi:10.1016/j.cmet.2013.04.020.
  77. Wang, L.; Yang, X.; Li, S.; Wang, Z.; Liu, Y.; Feng, J.; Zhu, Y.; Shen, Y. Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake. EMBO J. 2014, 33, 594–604, doi:10.1002/embj.201386523.
  78. Vais, H.; Payne, R.; Paudel, U.; Li, C.; Foskett, J.K. Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca2+ uptake. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 21731–21739, doi:10.1073/pnas.2005976117.
  79. Paillard, M.; Csordás, G.; Szanda, G.; Golenár, T.; Debattisti, V.; Bartok, A.; Wang, N.; Moffat, C.; Seifert, E.L.; Spät, A.; et al. Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU. Cell Rep. 2017, 18, 2291–2300, doi:10.1016/j.celrep.2017.02.032.
  80. Plovanich, M.; Bogorad, R.L.; Sancak, Y.; Kamer, K.J.; Strittmatter, L.; Li, A.A.; Girgis, H.S.; Kuchimanchi, S.; De Groot, J.; Speciner, L.; et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 2013, 8, e55785, doi:10.1371/journal.pone.0055785.
  81. Kamer, K.J.; Grabarek, Z.; Mootha, V.K. High‐affinity cooperative Ca 2+ binding by MICU 1– MICU 2 serves as an on–off switch for the uniporter. EMBO Rep. 2017, 18, 1397–1411, doi:10.15252/embr.201643748.
  82. Payne, R.; Hoff, H.; Roskowski, A.; Foskett, J.K. MICU2 Restricts Spatial Crosstalk between InsP 3 R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU. Cell Rep. 2017, 21, 3141–3154, doi:10.1016/j.celrep.2017.11.064.
  83. Mallilankaraman, K.; Cardenas, C.; Doonan, P.J.; Chandramoorthy, H.C.; Irrinki, K.M.; Golenar, T.; Csordas, G.; Madireddi, P.; Yang, J.; Muller, M.; et al. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat. Cell Biol. 2012, 14, 1336–1343, doi:10.1038/ncb2622.
  84. Ren, T.; Wang, J.; Zhang, H.; Yuan, P.; Zhu, J.; Wu, Y.; Huang, Q.; Guo, X.; Zhang, J.; Ji, L.; et al. MCUR1-Mediated Mitochondrial Calcium Signaling Facilitates Cell Survival of Hepatocellular Carcinoma via Reactive Oxygen Species-Dependent P53 Degradation. Antioxid. Redox Signal. 2018, 28, 1120–1136, doi:10.1089/ars.2017.6990.
  85. Tomar, D.; Dong, Z.; Shanmughapriya, S.; Koch, D.A.; Thomas, T.; Hoffman, N.E.; Timbalia, S.A.; Goldman, S.J.; Breves, S.L.; Corbally, D.P.; et al. MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. Cell Rep. 2016, 15, 1673–1685, doi:10.1016/j.celrep.2016.04.050.
  86. Paupe, V.; Prudent, J.; Dassa, E.P.; Rendon, O.Z.; Shoubridge, E.A. CCDC90A (MCUR1) Is a Cytochrome c Oxidase Assembly Factor and Not a Regulator of the Mitochondrial Calcium Uniporter. Cell Metab. 2015, 21, 109–116, doi:10.1016/j.cmet.2014.12.004.
  87. Bassi, M.T.; Manzoni, M.; Bresciani, R.; Pizzo, M.T.; Della Monica, A.; Barlati, S.; Monti, E.; Borsani, G. Cellular expression and alternative splicing of SLC25A23, a member of the mitochondrial Ca2+-dependent solute carrier gene family. Gene 2005, 345, 173–182, doi:10.1016/j.gene.2004.11.028.
  88. Harborne, S.P.D.; King, M.S.; Crichton, P.G.; Kunji, E.R.S. Calcium regulation of the human mitochondrial ATP-Mg/Pi carrier SLC25A24 uses a locking pin mechanism. Sci. Rep. 2017, 7, 45383, doi:10.1038/srep45383.
  89. Gunter, T.E.; Gunter, K.K. Uptake of Calcium by Mitochondria: Transport and Possible Function. IUBMB Life (International Union Biochem. Mol. Biol. Life) 2001, 52, 197–204, doi:10.1080/15216540152846000.
  90. Xu, Z.; Zhang, D.; He, X.; Huang, Y.; Shao, H. Transport of Calcium Ions into Mitochondria. Curr. Genomics 2016, 17, 215–219, doi:10.2174/1389202917666160202215748.
  91. Sparagna, G.C.; Gunter, K.K.; Sheu, S.-S.; Gunter, T.E. Mitochondrial Calcium Uptake from Physiological-type Pulses of Calcium. J. Biol. Chem. 1995, 270, 27510–27515, doi:10.1074/jbc.270.46.27510.
  92. Beutner, G.; Sharma, V.K.; Giovannucci, D.R.; Yule, D.I.; Sheu, S.-S. Identification of a Ryanodine Receptor in Rat Heart Mitochondria. J. Biol. Chem. 2001, 276, 21482–21488, doi:10.1074/jbc.M101486200.
  93. Beutner, G.; Sharma, V.K.; Lin, L.; Ryu, S.-Y.; Dirksen, R.T.; Sheu, S.-S. Type 1 ryanodine receptor in cardiac mitochondria: Transducer of excitation–metabolism coupling. Biochim. Biophys. Acta - Biomembr. 2005, 1717, 1–10, doi:10.1016/j.bbamem.2005.09.016.
  94. Babich, L.G.; Shlykov, S.G.; Kosterin, S.O. Ca ion transport in smooth muscle mitochondria. Ukr. Biochem. J. 2014, 86, 18–30, doi:10.15407/ubj86.06.018.
  95. Altschafl, B.A.; Beutner, G.; Sharma, V.K.; Sheu, S.-S.; Valdivia, H.H. The mitochondrial ryanodine receptor in rat heart: A pharmaco-kinetic profile. Biochim. Biophys. Acta - Biomembr. 2007, 1768, 1784–1795, doi:10.1016/j.bbamem.2007.04.011.
  96. Tamai, S.; Iida, H.; Yokota, S.; Sayano, T.; Kiguchiya, S.; Ishihara, N.; Hayashi, J.-I.; Mihara, K.; Oka, T. Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L. J. Cell Sci. 2008, 121, 2588–2600, doi:10.1242/jcs.026625.
  97. Endele, S.; Fuhry, M.; Pak, S.J.; Zabel, B.U.; Winterpacht, A. LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients. Genomics 1999, 60, 218–225, doi:10.1006/geno.1999.5881.
  98. Hasegawa, A.; van der Bliek, A.M. Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells. Hum. Mol. Genet. 2007, 16, 2061–2071, doi:10.1093/hmg/ddm154.
  99. Schlickum, S.; Moghekar, A.; Simpson, J.C.; Steglich, C.; O’Brien, R.J.; Winterpacht, A.; Endele, S.U. LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics 2004, 83, 254–261, doi:10.1016/j.ygeno.2003.08.013.
  100. Lin, Q.-T.; Stathopulos, P.B. Molecular Mechanisms of Leucine Zipper EF-Hand Containing Transmembrane Protein-1 Function in Health and Disease. Int. J. Mol. Sci. 2019, 20, doi:10.3390/ijms20020286.
  101. Doonan, P.J.; Chandramoorthy, H.C.; Hoffman, N.E.; Zhang, X.; Cardenas, C.; Shanmughapriya, S.; Rajan, S.; Vallem, S.; Chen, X.; Foskett, J.K.; et al. LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB J. Off. Publ. Fed. Am. Soc.  Exp. Biol. 2014, 28, 4936–4949, doi:10.1096/fj.14-256453.
  102. Jiang, D.; Zhao, L.; Clish, C.B.; Clapham, D.E. Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E2249-54, doi:10.1073/pnas.1308558110.
  103. Jiang, D.; Zhao, L.; Clapham, D.E. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 2009, 326, 144–147, doi:10.1126/science.1175145.
  104. Okamura, K.; Matsushita, S.; Kato, Y.; Watanabe, H.; Matsui, A.; Oka, T.; Matsuura, T. In vitro synthesis of the human calcium transporter Letm1 within cell-sized liposomes and investigation of its lipid dependency. J. Biosci. Bioeng. 2019, 127, 544–548, doi:10.1016/j.jbiosc.2018.11.003.
  105. Nowikovsky, K.; Bernardi, P. LETM1 in mitochondrial cation transport. Front. Physiol. 2014, 5, 83, doi:10.3389/fphys.2014.00083.
  106. De Marchi, U.; Santo-Domingo, J.; Castelbou, C.; Sekler, I.; Wiederkehr, A.; Demaurex, N. NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. J. Biol. Chem. 2014, 289, 20377–20385, doi:10.1074/jbc.M113.540898.
  107. Carafoli, E.; Tiozzo, R.; Lugli, G.; Crovetti, F.; Kratzing, C. The release of calcium from heart mitochondria by sodium. J. Mol. Cell. Cardiol. 1974, 6, 361—371, doi:10.1016/0022-2828(74)90077-7.
  108. Wingrove, D.E.; Gunter, T.E. Kinetics of mitochondrial calcium transport. I. Characteristics of the sodium-independent calcium efflux mechanism of liver mitochondria. J. Biol. Chem. 1986, 261, 15159–15165.
  109. Wingrove, D.E.; Gunter, T.E. Kinetics of mitochondrial calcium transport. II. A kinetic description of the sodium-dependent calcium efflux mechanism of liver mitochondria and inhibition by ruthenium red and by tetraphenylphosphonium. J. Biol. Chem. 1986, 261, 15166–15171.
  110. Hunter, D.R.; Haworth, R.A.; Hunter, D.R.; Haworth, R.A. The Ca2+-induced membrane transition in mitochondria. Arch. Biochem. Biophys. 1979, 195, 468–477, doi:10.1016/0003-9861(79)90373-4.
  111. Tsai, M.-F.; Jiang, D.; Zhao, L.; Clapham, D.; Miller, C. Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. J. Gen. Physiol. 2014, 143, 67–73, doi:10.1085/jgp.201311096.
  112. Nowikovsky, K.; Pozzan, T.; Rizzuto, R.; Scorrano, L.; Bernardi, P. The Pathophysiology of LETM1. J. Gen. Physiol. 2012, 139, 445–454, doi:10.1085/jgp.201110757.
  113. Palty, R.; Silverman, W.F.; Hershfinkel, M.; Caporale, T.; Sensi, S.L.; Parnis, J.; Nolte, C.; Fishman, D.; Shoshan-Barmatz, V.; Herrmann, S.; et al. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 436–441, doi:10.1073/pnas.0908099107.
  114. Luongo, T.S.; Lambert, J.P.; Gross, P.; Nwokedi, M.; Lombardi, A.A.; Shanmughapriya, S.; Carpenter, A.C.; Kolmetzky, D.; Gao, E.; van Berlo, J.H.; et al. The mitochondrial Na(+)/Ca(2+) exchanger is essential for Ca(2+) homeostasis and viability. Nature 2017, 545, 93–97, doi:10.1038/nature22082.
  115. Kostic, M.; Sekler, I. Functional properties and mode of regulation of the mitochondrial Na+/Ca2+ exchanger, NCLX. Semin. Cell Dev. Biol. 2019, 94, 59–65, doi:10.1016/j.semcdb.2019.01.009.
  116. Palty, R.; Ohana, E.; Hershfinkel, M.; Volokita, M.; Elgazar, V.; Beharier, O.; Silverman, W.F.; Argaman, M.; Sekler, I. Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger. J. Biol. Chem. 2004, 279, 25234—25240, doi:10.1074/jbc.m401229200.
  117. Sheng, J.-Z.; Prinsen, C.F.M.; Clark, R.B.; Giles, W.R.; Schnetkamp, P.P.M. Na+-Ca2+-K+ Currents Measured in Insect Cells Transfected with the Retinal Cone or Rod Na+-Ca2+-K+ Exchanger cDNA. Biophys. J. 2000, 79, 1945–1953, doi:10.1016/S0006-3495(00)76443-5.
  118. Gunter, T.E.; Yule, D.I.; Gunter, K.K.; Eliseev, R.A.; Salter, J.D. Calcium and mitochondria. FEBS Lett. 2004, 567, 96–102, doi:10.1016/j.febslet.2004.03.071.
  119. Takeuchi, A.; Kim, B.; Matsuoka, S. The destiny of Ca2+ released by mitochondria. J. Physiol. Sci. 2015, 65, 11–24, doi:10.1007/s12576-014-0326-7.
  120. Haworth, R.A.; Hunter, D.R.; Berkoff, H.A. Na + releases Ca 2+ from liver, kidney and lung mitochondria. FEBS Lett. 1980, 110, 216–218, doi:10.1016/0014-5793(80)80076-7.
  121. Zhang, Y.; Lipton, P. Cytosolic Ca2+ changes during in vitro ischemia in rat hippocampal slices: major roles for glutamate and Na+-dependent Ca2+ release from mitochondria. J. Neurosci. 1999, 19, 3307–3315.
  122. Islam, M.M.; Takeuchi, A.; Matsuoka, S. Membrane current evoked by mitochondrial Na+–Ca2+ exchange in mouse heart. J. Physiol. Sci. 2020, 70, 24, doi:10.1186/s12576-020-00752-3.
  123. Samanta, K.; Mirams, G.R.; Parekh, A.B. Sequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria. Nat. Commun. 2018, 9, 156, doi:10.1038/s41467-017-02638-2.
  124. Kolomiets, O. V.; Danylovych, Y. V.; Danylovych, H. V.; Kosterin, S.O. Ca(2+)/H(+)-exchange in myometrium mitochondria. Ukr. Biochem. J. 2014, 86, 41–48, doi:10.15407/ubj86.03.041.
  125. Kandaurova, N.V. Ca2+-induced Changes of Membrane Potential of Myometrium Mitochondria, 2011.
  126. Gunter, K.K.; Zuscik, M.J.; Gunter, T.E. The Na(+)-independent Ca2+ efflux mechanism of liver mitochondria is not a passive Ca2+/2H+ exchanger. J. Biol. Chem. 1991, 266, 21640–21648.
  127. Huang, E.; Qu, D.; Huang, T.; Rizzi, N.; Boonying, W.; Krolak, D.; Ciana, P.; Woulfe, J.; Klein, C.; Slack, R.S.; et al. PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nat. Commun. 2017, 8, 1399, doi:10.1038/s41467-017-01435-1.
  128. Pérez, M.J.; Quintanilla, R.A. Development or disease: duality of the mitochondrial permeability transition pore. Dev. Biol. 2017, 426, 1–7, doi:10.1016/j.ydbio.2017.04.018.
  129. Britti, E.; Delaspre, F.; Tamarit, J.; Ros, J. Mitochondrial calcium signalling and neurodegenerative diseases. Neuronal Signal. 2018, 2, doi:10.1042/NS20180061.
  130. Biasutto, L.; Azzolini, M.; Szabò, I.; Zoratti, M. The mitochondrial permeability transition pore in AD 2016: An update. Biochim. Biophys. Acta - Mol. Cell Res. 2016, 1863, 2515–2530, doi:10.1016/j.bbamcr.2016.02.012.
  131. Li, Y.; Sun, J.; Wu, R.; Bai, J.; Hou, Y.; Zeng, Y.; Zhang, Y.; Wang, X.; Wang, Z.; Meng, X. Mitochondrial MPTP: A Novel Target of Ethnomedicine for Stroke Treatment by Apoptosis Inhibition. Front. Pharmacol. 2020, 11, 352, doi:10.3389/fphar.2020.00352.
  132. Hurst, S.; Hoek, J.; Sheu, S.-S. Mitochondrial Ca2+ and regulation of the permeability transition pore. J. Bioenerg. Biomembr. 2017, 49, 27–47, doi:10.1007/s10863-016-9672-x.
  133. Altschuld, R.A.; Hohl, C.M.; Castillo, L.C.; Garleb, A.A.; Starling, R.C.; Brierley, G.P. Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am. J. Physiol. Circ. Physiol. 1992, 262, H1699–H1704, doi:10.1152/ajpheart.1992.262.6.H1699.
  134. Mnatsakanyan, N.; Beutner, G.; Porter, G.A.; Alavian, K.N.; Jonas, E.A. Physiological roles of the mitochondrial permeability transition pore. J. Bioenerg. Biomembr. 2017, 49, 13–25, doi:10.1007/s10863-016-9652-1.
  135. Basso, E.; Fante, L.; Fowlkes, J.; Petronilli, V.; Forte, M.A.; Bernardi, P. Properties of the Permeability Transition Pore in Mitochondria Devoid of Cyclophilin D. J. Biol. Chem. 2005, 280, 18558–18561, doi:10.1074/jbc.C500089200.
  136. Shanmughapriya, S.; Rajan, S.; Hoffman, N.E.; Higgins, A.M.; Tomar, D.; Nemani, N.; Hines, K.J.; Smith, D.J.; Eguchi, A.; Vallem, S.; et al. SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore. Mol. Cell 2015, 60, 47–62, doi:10.1016/j.molcel.2015.08.009.
  137. Baines, C.P.; Kaiser, R.A.; Purcell, N.H.; Blair, N.S.; Osinska, H.; Hambleton, M.A.; Brunskill, E.W.; Sayen, M.R.; Gottlieb, R.A.; Dorn, G.W.; et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005, 434, 658–662, doi:10.1038/nature03434.
  138. Nakagawa, T.; Shimizu, S.; Watanabe, T.; Yamaguchi, O.; Otsu, K.; Yamagata, H.; Inohara, H.; Kubo, T.; Tsujimoto, Y. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005, 434, 652–658, doi:10.1038/nature03317.
  139. Schinzel, A.C.; Takeuchi, O.; Huang, Z.; Fisher, J.K.; Zhou, Z.; Rubens, J.; Hetz, C.; Danial, N.N.; Moskowitz, M.A.; Korsmeyer, S.J. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl. Acad. Sci. 2005, 102, 12005–12010, doi:10.1073/pnas.0505294102.
  140. Alam, M.R.; Baetz, D.; Ovize, M. Cyclophilin D and myocardial ischemia–reperfusion injury: A fresh perspective. J. Mol. Cell. Cardiol. 2015, 78, 80–89, doi:10.1016/j.yjmcc.2014.09.026.
  141. Kokoszka, J.E.; Waymire, K.G.; Levy, S.E.; Sligh, J.E.; Cai, J.; Jones, D.P.; MacGregor, G.R.; Wallace, D.C. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004, 427, 461–465, doi:10.1038/nature02229.
  142. Karch, J.; Bround, M.J.; Khalil, H.; Sargent, M.A.; Latchman, N.; Terada, N.; Peixoto, P.M.; Molkentin, J.D. Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD. Sci. Adv. 2019, 5, eaaw4597, doi:10.1126/sciadv.aaw4597.
  143. Bround, M.J.; Bers, D.M.; Molkentin, J.D. A 20/20 view of ANT function in mitochondrial biology and necrotic cell death. J. Mol. Cell. Cardiol. 2020, 144, A3–A13, doi:10.1016/j.yjmcc.2020.05.012.
  144. Kwong, J.Q.; Davis, J.; Baines, C.P.; Sargent, M.A.; Karch, J.; Wang, X.; Huang, T.; Molkentin, J.D. Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ. 2014, 21, 1209–1217, doi:10.1038/cdd.2014.36.
  145. Varanyuwatana, P.; Halestrap, A.P. The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. Mitochondrion 2012, 12, 120–125, doi:10.1016/j.mito.2011.04.006.
  146. Hurst, S.; Baggett, A.; Csordas, G.; Sheu, S.-S. SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca 2+ influx, and regulation of mitochondrial permeability transition pore opening. J. Biol. Chem. 2019, 294, 10807–10818, doi:10.1074/jbc.RA118.006443.
  147. Leung, A.W.C.; Varanyuwatana, P.; Halestrap, A.P. The Mitochondrial Phosphate Carrier Interacts with Cyclophilin D and May Play a Key Role in the Permeability Transition. J. Biol. Chem. 2008, 283, 26312–26323, doi:10.1074/jbc.M805235200.
  148. Giorgio, V.; von Stockum, S.; Antoniel, M.; Fabbro, A.; Fogolari, F.; Forte, M.; Glick, G.D.; Petronilli, V.; Zoratti, M.; Szabo, I.; et al. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl. Acad. Sci. 2013, 110, 5887–5892, doi:10.1073/pnas.1217823110.
  149. Bonora, M.; Bononi, A.; De Marchi, E.; Giorgi, C.; Lebiedzinska, M.; Marchi, S.; Patergnani, S.; Rimessi, A.; Suski, J.M.; Wojtala, A.; et al. Role of the c subunit of the F O ATP synthase in mitochondrial permeability transition. Cell Cycle 2013, 12, 674–683, doi:10.4161/cc.23599.
  150. CROMPTON, M.; COSTI, A. Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload. Eur. J. Biochem. 1988, 178, 489–501, doi:10.1111/j.1432-1033.1988.tb14475.x.
  151. Carraro, M.; Giorgio, V.; Šileikytė, J.; Sartori, G.; Forte, M.; Lippe, G.; Zoratti, M.; Szabò, I.; Bernardi, P. Channel Formation by Yeast F-ATP Synthase and the Role of Dimerization in the Mitochondrial Permeability Transition. J. Biol. Chem. 2014, 289, 15980–15985, doi:10.1074/jbc.C114.559633.
  152. Zhou, W.; Marinelli, F.; Nief, C.; Faraldo-Gómez, J.D. Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore. Elife 2017, 6, doi:10.7554/eLife.23781.
  153. He, J.; Ford, H.C.; Carroll, J.; Ding, S.; Fearnley, I.M.; Walker, J.E. Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase. Proc. Natl. Acad. Sci. 2017, 114, 3409–3414, doi:10.1073/pnas.1702357114.
  154. He, J.; Carroll, J.; Ding, S.; Fearnley, I.M.; Walker, J.E. Permeability transition in human mitochondria persists in the absence of peripheral stalk subunits of ATP synthase. Proc. Natl. Acad. Sci. 2017, 114, 9086–9091, doi:10.1073/pnas.1711201114.
  155. Bonora, M.; Wieckowski, M.R.; Chinopoulos, C.; Kepp, O.; Kroemer, G.; Galluzzi, L.; Pinton, P. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 2015, 34, 1475–1486, doi:10.1038/onc.2014.96.
  156. Halestrap, A.P.; Richardson, A.P. The mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury. J. Mol. Cell. Cardiol. 2015, 78, 129–141, doi:10.1016/j.yjmcc.2014.08.018.
  157. Bernardi, P. The mitochondrial permeability transition pore: a mystery solved? Front. Physiol. 2013, 4, doi:10.3389/fphys.2013.00095.
  158. Jonas, E.A.; Porter, G.A.; Beutner, G.; Mnatsakanyan, N.; Alavian, K.N. Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase. Pharmacol. Res. 2015, 99, 382–392, doi:10.1016/j.phrs.2015.04.013.
  159. Elustondo, P.A.; Nichols, M.; Negoda, A.; Thirumaran, A.; Zakharian, E.; Robertson, G.S.; Pavlov, E. V Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate. Cell Death Discov. 2016, 2, 16070, doi:10.1038/cddiscovery.2016.70.
  160. Alavian, K.N.; Beutner, G.; Lazrove, E.; Sacchetti, S.; Park, H.-A.; Licznerski, P.; Li, H.; Nabili, P.; Hockensmith, K.; Graham, M.; et al. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc. Natl. Acad. Sci. 2014, 111, 10580–10585, doi:10.1073/pnas.1401591111.
  161. Chinopoulos, C. Mitochondrial permeability transition pore: Back to the drawing board. Neurochem. Int. 2018, 117, 49–54, doi:10.1016/j.neuint.2017.06.010.
  162. Ichas, F.; Jouaville, L.S.; Mazat, J.-P. Mitochondria Are Excitable Organelles Capable of Generating and Conveying Electrical and Calcium Signals. Cell 1997, 89, 1145–1153, doi:10.1016/S0092-8674(00)80301-3.
  163. Lu, X.; Kwong, J.Q.; Molkentin, J.D.; Bers, D.M. Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings. Circ. Res. 2016, 118, 834–841, doi:10.1161/CIRCRESAHA.115.308093.
  164. Ichas, F.; Mazat, J.-P. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim. Biophys. Acta - Bioenerg. 1998, 1366, 33–50, doi:10.1016/S0005-2728(98)00119-4.
  165. Gainutdinov, T.; Molkentin, J.D.; Siemen, D.; Ziemer, M.; Debska-Vielhaber, G.; Vielhaber, S.; Gizatullina, Z.; Orynbayeva, Z.; Gellerich, F.N. Knockout of cyclophilin D in Ppif−/− mice increases stability of brain mitochondria against Ca2+ stress. Arch. Biochem. Biophys. 2015, 579, 40–46, doi:10.1016/j.abb.2015.05.009.
  166. Bernardi, P.; von Stockum, S. The permeability transition pore as a Ca2+ release channel: New answers to an old question. Cell Calcium 2012, 52, 22–27, doi:10.1016/j.ceca.2012.03.004.
  167. Korge, P.; Yang, L.; Yang, J.-H.; Wang, Y.; Qu, Z.; Weiss, J.N. Protective Role of Transient Pore Openings in Calcium Handling by Cardiac Mitochondria. J. Biol. Chem. 2011, 286, 34851–34857, doi:10.1074/jbc.M111.239921.
  168. Elrod, J.W.; Wong, R.; Mishra, S.; Vagnozzi, R.J.; Sakthievel, B.; Goonasekera, S.A.; Karch, J.; Gabel, S.; Farber, J.; Force, T.; et al. Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice. J. Clin. Invest. 2010, 120, 3680–3687, doi:10.1172/JCI43171.
  169. Lamb, H.M. Double agents of cell death: novel emerging functions of apoptotic regulators. FEBS J. 2020, doi:10.1111/febs.15308.
  170. Baines, C.P.; Gutiérrez-Aguilar, M. The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore. Cell Calcium 2018, 73, 121–130, doi:10.1016/j.ceca.2018.05.003.
  171. Zorow, D.B.; Kinnally, K.W.; Perini, S.; Tedeschi, H. Multiple conductance levels in rat heart inner mitochondrial membranes studied by patch clamping. Biochim. Biophys. Acta - Biomembr. 1992, 1105, 263–270, doi:10.1016/0005-2736(92)90203-X.
  172. Petronilli, V.; Miotto, G.; Canton, M.; Brini, M.; Colonna, R.; Bernardi, P.; Di Lisa, F. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys. J. 1999, 76, 725–734, doi:10.1016/S0006-3495(99)77239-5.
  173. Xu, H.; Cui, S.; Zhang, Y.; Ren, J. Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications. Acta Pharmacol. Sin. 2020, doi:10.1038/s41401-020-0476-5.
  174. Kinnally, K.W.; Peixoto, P.M.; Ryu, S.-Y.; Dejean, L.M. Is mPTP the gatekeeper for necrosis, apoptosis, or both? Biochim. Biophys. Acta - Mol. Cell Res. 2011, 1813, 616–622, doi:10.1016/j.bbamcr.2010.09.013.
  175. Bernardi, P.; Rasola, A.; Forte, M.; Lippe, G. The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology. Physiol. Rev. 2015, 95, 1111–1155, doi:10.1152/physrev.00001.2015.
  176. Elrod, J.W.; Molkentin, J.D. Physiologic Functions of Cyclophilin D and the Mitochondrial Permeability Transition Pore. Circ. J. 2013, 77, 1111–1122, doi:10.1253/circj.CJ-13-0321.
  177. Halestrap, A. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc. Res. 2004, 61, 372–385, doi:10.1016/S0008-6363(03)00533-9.
  178. Szabó, I.; Zoratti, M. The mitochondrial permeability transition pore may comprise VDAC molecules. FEBS Lett. 1993, 330, 201–205, doi:10.1016/0014-5793(93)80273-W.
  179. Crompton, M.; Virji, S.; Ward, J.M. Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur. J. Biochem. 1998, 258, 729–735, doi:10.1046/j.1432-1327.1998.2580729.x.
  180. Zheng, Y.; Shi, Y.; Tian, C.; Jiang, C.; Jin, H.; Chen, J.; Almasan, A.; Tang, H.; Chen, Q. Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene 2004, 23, 1239–1247, doi:10.1038/sj.onc.1207205.
  181. Chaudhuri, A.D.; Choi, D.C.; Kabaria, S.; Tran, A.; Junn, E. MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression. J. Biol. Chem. 2016, 291, 6483–6493, doi:10.1074/jbc.M115.691352.
  182. Zhou, H.; Hu, S.; Jin, Q.; Shi, C.; Zhang, Y.; Zhu, P.; Ma, Q.; Tian, F.; Chen, Y. Mff‐Dependent Mitochondrial Fission Contributes to the Pathogenesis of Cardiac Microvasculature Ischemia/Reperfusion Injury via Induction of mROS‐Mediated Cardiolipin Oxidation and HK2/VDAC1 Disassociation‐Involved mPTP Opening. J. Am. Heart Assoc. 2017, 6, doi:10.1161/JAHA.116.005328.
  183. Tan, W.; Colombini, M. VDAC closure increases calcium ion flux. Biochim. Biophys. Acta - Biomembr. 2007, 1768, 2510–2515, doi:10.1016/j.bbamem.2007.06.002.
  184. Tikunov, A.; Johnson, C.B.; Pediaditakis, P.; Markevich, N.; Macdonald, J.M.; Lemasters, J.J.; Holmuhamedov, E. Closure of VDAC causes oxidative stress and accelerates the Ca2+-induced mitochondrial permeability transition in rat liver mitochondria. Arch. Biochem. Biophys. 2010, 495, 174–181, doi:10.1016/j.abb.2010.01.008.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback