Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mitochondrial ion channels as oncological targets

Oncogene volume 33, pages 5569–5581 (2014)Cite this article

Subjects

Abstract

Mitochondria, the key bioenergetic intracellular organelles, harbor a number of proteins with proven or hypothetical ion channel functions. Growing evidence points to the important contribution of these channels to the regulation of mitochondrial function, such as ion homeostasis imbalances profoundly affecting energy transducing processes, reactive oxygen species production and mitochondrial integrity. Given the central role of mitochondria in apoptosis, their ion channels with the potential to compromise mitochondrial function have become promising targets for the treatment of malignancies. Importantly, in vivo evidence demonstrates the involvement of the proton-transporting uncoupling protein, a mitochondrial potassium channel, the outer membrane located porin and the permeability transition pore in tumor progression/control. In this review, we focus on mitochondrial channels that have been assigned a definite role in cell death regulation and possess clear oncological relevance. Overall, based on in vivo and in vitro genetic and pharmacological evidence, mitochondrial ion channels are emerging as promising targets for cancer treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Galluzzi L, Kepp O, Kroemer G . Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 2012; 13: 780–788.

    CAS  PubMed  Google Scholar 

  2. Fulda S, Galluzzi L, Kroemer G . Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 2010; 9: 447–464.

    CAS  PubMed  Google Scholar 

  3. Bender T, Martinou JC . Where killers meet—permeabilization of the outer mitochondrial membrane during apoptosis. Cold Spring Harb Perspect Biol 2013; 5: a011106.

    PubMed  PubMed Central  Google Scholar 

  4. Dejean LM, Ryu SY, Martinez-Caballero S, Teijido O, Peixoto PM, KW Kinnally . MAC and Bcl-2 family proteins conspire in a deadly plot. Biochim Biophys Acta 2010; 1797: 1231–1238.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Starkov AA . The role of mitochondria in reactive oxygen species metabolism and signaling. Ann NY Acad Sci 2008; 1147: 37–52.

    CAS  PubMed  Google Scholar 

  6. Murphy MP . How mitochondria produce reactive oxygen species. Biochem J 2009; 417: 1–13.

    CAS  PubMed  Google Scholar 

  7. Kadenbach B . Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta 2003; 1604: 77–94.

    CAS  PubMed  Google Scholar 

  8. Malinska D, Mirandola SR, Kunz WS . Mitochondrial potassium channels and reactive oxygen species. FEBS Lett 2010; 584: 2043–2048.

    CAS  PubMed  Google Scholar 

  9. Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE . Mitochondria and reactive oxygen species. Free Radic Biol Med 2009; 47: 333–343.

    CAS  PubMed  Google Scholar 

  10. Demin OV, Kholodenko BN, Skulachev VP . A model of O2.-generation in the complex III of the electron transport chain. Mol Cell Biochem 1998; 184: 21–33.

    CAS  PubMed  Google Scholar 

  11. O-Uchi J, Ryu SY, Jhun BS, Hurst S, Sheu SS . Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling. Antioxid Redox Signal 2013, PMID: 24180309.

  12. Orr AL, Quinlan CL, Perevoshchikova IV, Brand MD . A refined analysis of superoxide production by mitochondrial sn-glycerol 3-phosphate dehydrogenase. J Biol Chem 2012; 287: 42921–42935.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD . Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol 2013; 1: 304–312.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fiaschi T, Chiarugi P . Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. Int J Cell Biol 2012; 2012: 762825.

    PubMed  PubMed Central  Google Scholar 

  15. Biasutto L, Szabo I, Zoratti M . Mitochondrial effects of plant-made compounds. Antioxid Redox Signal 2012; 15: 3039–3059.

    Google Scholar 

  16. Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011; 334: 1278–1283.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, Yodoi J . Redox control of cell death. Antioxid Redox Signal 2002; 4: 405–414.

    CAS  PubMed  Google Scholar 

  18. Circu ML, Aw TY . Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 2010; 48: 749–762.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Panieri E, Gogvadze V, Norberg E, Venkatesh R, Orrenius S, Zhivotovsky B . Reactive oxygen species generated in different compartments induce cell death, survival, or senescence. Free Radic Biol Med 2013; 57: 176–187.

    CAS  PubMed  Google Scholar 

  20. Bialik S, Kimchi A . The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 2006; 75: 189–210.

    CAS  PubMed  Google Scholar 

  21. Takeda K, Noguchi T, Naguro I, Ichijo H . Apoptosis signal-regulating kinase 1 in stress and immune response. Annu Rev Pharmacol Toxicol 2008; 48: 199–225.

    CAS  PubMed  Google Scholar 

  22. Ghibelli L, Diederich M . Multistep and multitask Bax activation. Mitochondrion 2010; 10: 604–613.

    CAS  PubMed  Google Scholar 

  23. Scorrano L . Opening the doors to cytochrome c: changes in mitochondrial shape and apoptosis. Int J Biochem Cell Biol 2009; 41: 1875–1883.

    CAS  PubMed  Google Scholar 

  24. Landes T, Martinou JC . Mitochondrial outer membrane permeabilization during apoptosis: the role of mitochondrial fission. Biochim Biophys Acta 2011; 1813: 540–545.

    CAS  PubMed  Google Scholar 

  25. Trachootham D, Alexandre J, Huang P . Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 579–591.

    CAS  PubMed  Google Scholar 

  26. Ralph SJ, Rodríguez-Enríquez S, Neuzil J, Saavedra E, Moreno-Sánchez R . The causes of cancer revisited: ‘mitochondrial malignancy’ and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. Mol Aspects Med 2010; 31: 145–170.

    CAS  PubMed  Google Scholar 

  27. Ralph SJ, Moreno-Sánchez R, Neuzil J, Rodríguez-Enríquez S . Inhibitors of succinate: quinone reductase/Complex II regulate production of mitochondrial reactive oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death. Pharm Res 2011; 28: 2695–2730.

    CAS  PubMed  Google Scholar 

  28. Wang J, Yi J . Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther 2008; 7: 1875–1884.

    CAS  PubMed  Google Scholar 

  29. Kirichok Y, Krapivinsky G, Clapham DE . The mitochondrial calcium uniporter is a highly selective ion channel. Nature 2004; 427: 360–364.

    CAS  PubMed  Google Scholar 

  30. Gunter TE, Buntinas L, Sparagna G, Eliseev R, Gunter K . Mitochondrial calcium transport: mechanisms and functions. Cell Calcium 2000; 28: 285–296.

    CAS  PubMed  Google Scholar 

  31. Drago I, Pizzo P, Pozzan T . After half a century mitochondrial calcium in- and efflux machineries reveal themselves. EMBO J 2011; 30: 4119–4125.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kinnally KW, Peixoto PM, Ryu SY, Dejean LM . Is mMPTP the gatekeeper for necrosis, apoptosis, or both? Biochim Biophys Acta 2011; 1813: 616–622.

    CAS  PubMed  Google Scholar 

  33. Rasola A, Bernardi P . Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 2011; 50: 222–233.

    CAS  PubMed  Google Scholar 

  34. Peng TI, Jou MJ . Oxidative stress caused by mitochondrial calcium overload. Ann NY Acad Sci 2010; 1201: 183–188.

    CAS  PubMed  Google Scholar 

  35. Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O'Rourke B . Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ Res 2006; 99: 172–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nichols BJ, Denton RM . Towards the molecular basis for the regulation of mitochondrial dehydrogenases by calcium ions. Mol Cell Biochem 1995; 149-150: 203–212.

    CAS  PubMed  Google Scholar 

  37. Denton RM . Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 2009; 1787: 1309–1316.

    CAS  PubMed  Google Scholar 

  38. Pedersen PL . The cancer cell’s ‘power plants’ as promising therapeutic targets: an overview. J Bioenerg Biomembr 2007; 39: 1–12.

    Article  CAS  PubMed  Google Scholar 

  39. Wallace DC . Mitochondria and cancer. Nat Rev Cancer. 2012; 12: 685–698.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Halestrap AP . The regulation of the oxidation of fatty acids and other substrates in rat heart mitochondria by changes in the matrix volume induced by osmotic strength, valinomycin and Ca2+. Biochem J 1987; 244: 159–164.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Aon MA, Cortassa S, Wei AC, Grunnet M, O'Rourke B . Energetic performance is improved by specific activation of K+ fluxes through K(Ca) channels in heart mitochondria. Biochim Biophys Acta 2010; 1797: 71–80.

    CAS  PubMed  Google Scholar 

  42. Venediktova N, Shigaeva M, Belova S, Belosludtsev K, Belosludtseva N, Gorbacheva O, Lezhnev E, Lukyanova L, Mironova G . Oxidative phosphorylation and ion transport in the mitochondria of two strains of rats varying in their resistance to stress and hypoxia. Mol Cell Biochem 2013; 383: 261–269.

    CAS  PubMed  Google Scholar 

  43. Bednarczyk P, Wieckowski MR, Broszkiewicz M, Skowronek K, Siemen D, Szewczyk A . Putative structural and functional coupling of the mitochondrial BKCa channel to the respiratory chain. PLoS One 2013; 8: e68125.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 2013; 155: 160–171.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Perevoshchikova IV, Zorov SD, Kotova EA, Zorov DB, Antonenko YN . Hexokinase inhibits flux of fluorescently labeled ATP through mitochondrial outer membrane porin. FEBS Lett 2010; 584: 2397–2402.

    CAS  PubMed  Google Scholar 

  46. Lemasters JJ, Holmuhamedov E . Voltage-dependent anion channel (VDAC) as mitochondrial governator—thinking outside the box. Biochim Biophys Acta 2006; 1762: 181–190.

    CAS  PubMed  Google Scholar 

  47. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V . In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 2004; 377: 347–355.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N . VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 2010; 31: 227–285.

    CAS  PubMed  Google Scholar 

  49. Zoratti M, De Marchi U, Gulbins E, Szabò I . Novel channels of the inner mitochondrial membrane. Biochim Biophys Acta 2009; 1787: 351–363.

    CAS  PubMed  Google Scholar 

  50. Szabò I, Leanza L, Gulbins E, Zoratti M . Physiology of potassium channels in the inner membrane of mitochondria. Pflugers Arch 2012; 463: 231–246.

    PubMed  Google Scholar 

  51. Rizzuto R, De Stefani D, Raffaello A, Mammucari C . Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012; 13: 566–578.

    CAS  PubMed  Google Scholar 

  52. Tan W . VDAC blockage by phosphorothioate oligonucleotides and its implication in apoptosis. Biochim Biophys Acta 2012; 1818: 1555–1561.

    CAS  PubMed  Google Scholar 

  53. Grills C, Jithesh PV, Blayney J, Zhang SD, Fennell DA . Gene expression meta-analysis identifies VDAC1 as a predictor of poor outcome in early stage non-small cell lung cancer. PLoS One 2011; 6: e14635.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. McCommis KS, Baines CP . The role of VDAC in cell death: friend or foe? Biochim Biophys Acta 2012; 1818: 1444–1450.

    CAS  PubMed  Google Scholar 

  55. Shoshan-Barmatz V, Golan M . Mitochondrial VDAC1: function in cell life and death and a target for cancer therapy. Curr Med Chem 2012; 19: 714–735.

    CAS  PubMed  Google Scholar 

  56. Shoshan-Barmatz V, Mizrachi D . VDAC1: from structure to cancer therapy. Front Oncol 2012; 2: 164.

    PubMed  PubMed Central  Google Scholar 

  57. Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med 2011; 208: 313–326.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Koren I, Raviv Z, Shoshan-Barmatz V . Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo. Cancer Biol Ther 2010; 9: 1046–1052.

    CAS  PubMed  Google Scholar 

  59. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V . The voltage-dependent anion channel-1 modulates apoptotic cell death. Cell Death Differ 2005; 12: 751–760.

    CAS  PubMed  Google Scholar 

  60. Mader A, Abu-Hamad S, Arbel N, Gutiérrez-Aguilar M, Shoshan-Barmatz V . Dominant-negative VDAC1 mutants reveal oligomeric VDAC1 to be the active unit in mitochondria-mediated apoptosis. Biochem J 2010; 429: 147–155.

    CAS  PubMed  Google Scholar 

  61. Sharaf el dein O, Gallerne C, Brenner C, Lemaire C . Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. Biochem Pharmacol 2012; 83: 1172–1182.

    CAS  PubMed  Google Scholar 

  62. Pastorino JG, Shulga N, Hoek JB . Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 2002; 277: 7610–7618.

    CAS  PubMed  Google Scholar 

  63. Gall JM, Wong V, Pimental DR, Havasi A, Wang Z, Pastorino JG et al. Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress. Kidney Int 2011; 79: 1207–1216.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chiara F, Castellaro D, Marin O, Petronilli V, Brusilow WS, Juhaszova M et al. Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS One 2008; 3: e1852.

    PubMed  PubMed Central  Google Scholar 

  65. Fingrut O, Flescher E . Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells. Leukemia 2002; 16: 608–616.

    CAS  PubMed  Google Scholar 

  66. Klippel S, Jakubikova J, Delmore J, Ooi M, McMillin D, Kastritis E et al. Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells. Br J Haematol 2012; 159: 340–351.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Palmieri B, Iannitti T, Capone S, Flescher E . A preliminary study of the local treatment of preneoplastic and malignant skin lesions using methyl jasmonate. Eur Rev Med Pharmacol Sci 2011; 15: 333–336.

    CAS  PubMed  Google Scholar 

  68. Kim JH, Lee SY, Oh SY, Han SI, Park HG, Yoo MA et al. Methyl jasmonate induces apoptosis through induction of Bax/Bcl-XS and activation of caspase-3 via ROS production in A549 cells. Oncol Rep 2004; 12: 1233–1238.

    CAS  PubMed  Google Scholar 

  69. Tong QS, Jiang GS, Zheng LD, Tang ST, Cai JB, Liu Y et al. Methyl jasmonate downregulates expression of proliferating cell nuclear antigen and induces apoptosis in human neuroblastoma cell lines. Anticancer Drugs 2008; 19: 573–581.

    CAS  PubMed  Google Scholar 

  70. Davies NJ, Hayden RE, Simpson PJ, Birtwistle J, Mayer K, Ride JP et al. AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects. Cancer Res 2009; 69: 4769–4775.

    CAS  PubMed  Google Scholar 

  71. Ji Q, Chang L, VanDenBerg D, Stanczyk FZ, Stolz A . Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism. Prostate 2003; 54: 275–289.

    CAS  PubMed  Google Scholar 

  72. Vihko P, Herrala A, Härkönen P, Isomaa V, Kaija H, Kurkela R et al. Enzymes as modulators in malignant transformation. J Steroid Biochem Mol Biol 2005; 93: 277–283.

    CAS  PubMed  Google Scholar 

  73. De Marchi U, Sassi N, Fioretti B, Catacuzzeno L, Cereghetti GM, Szabò I et al. Intermediate conductance Ca2+-activated potassium channel (KCa3.1) in the inner mitochondrial membrane of human colon cancer cells. Cell Calcium 2009; 45: 509–516.

    CAS  PubMed  Google Scholar 

  74. Quast SA, Berger A, Buttstädt N, Friebel K, Schönherr R, Eberle J . General sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. PLoS One 2012; 7: e39290.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gelb BD, Adams V, Jones SN, Griffin LD, MacGregor GR, McCabe ER . Targeting of hexokinase 1 to liver and hepatoma mitochondria. Proc Natl Acad Sci USA 1992; 89: 202–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 2004; 16: 819–830.

    CAS  PubMed  Google Scholar 

  77. Pedersen PL . 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective ‘small molecule’ anti-cancer agent taken from labside to bedside: introduction to a special issue. J Bioenerg Biomembr 2012; 44: 1–6.

    CAS  PubMed  Google Scholar 

  78. Shoshan MC . 3-Bromopyruvate: targets and outcomes. J Bioenerg Biomembr 2012; 44: 7–15.

    CAS  PubMed  Google Scholar 

  79. Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL . A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr 2012; 44: 163–170.

    CAS  PubMed  Google Scholar 

  80. Cardaci S, Desideri E, Ciriolo MR . Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug. J Bioenerg Biomembr 2012; 44: 17–29.

    CAS  PubMed  Google Scholar 

  81. Galluzzi L, Kepp O, Heiden MG, Kroemer G . Metabolic targets for cancer therapy. Nat Rev Drug Discov 2013; 12: 829–846.

    CAS  PubMed  Google Scholar 

  82. Tang Z, Yuan S, Hu Y, Zhang H, Wu W, Zeng Z et al. Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester. J Bioenerg Biomembr 2012; 44: 117–125.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Rodrigues-Ferreira C, da Silva AP, Galina A . Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase. J Bioenerg Biomembr 2012; 44: 39–49.

    CAS  PubMed  Google Scholar 

  84. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004; 324: 269–275.

    CAS  PubMed  Google Scholar 

  85. Lau E, Kluger H, Varsano T, Lee KY, Scheffler I, Rimm DL et al. PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 2012; 148: 543–555.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864–868.

    PubMed  PubMed Central  Google Scholar 

  87. Tikunov A, Johnson CB, Pediaditakis P, Markevich N, Macdonald JM, Lemasters JJ et al. Closure of VDAC causes oxidative stress and accelerates the Ca(2+)-induced mitochondrial permeability transition in rat liver mitochondria. Arch Biochem Biophys 2010; 495: 174–181.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Simamura E, Shimada H, Hatta T, Hirai K . Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents. J Bioenerg Biomembr 2008; 40: 213–217.

    CAS  PubMed  Google Scholar 

  89. Tsujimoto Y, Shimizu S . VDAC regulation by the Bcl-2 family of proteins. Cell Death Differ 2000; 7: 1174–1181.

    CAS  PubMed  Google Scholar 

  90. Martinez-Caballero S, Dejean LM, Kinnally MS, Oh KJ, Mannella CA, Kinnally KW . Assembly of the mitochondrial apoptosis-induced channel, MAC. J Biol Chem 2009; 284: 12235–12245.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L et al. Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene 2008; 27: 4221–4232.

    CAS  PubMed  Google Scholar 

  92. Tomasello F, Messina A, Lartigue L, Schembri L, Medina C, Reina S et al. Outer membrane VDAC1 controls permeability transition of the inner mitochondrial membrane in cellulo during stress-induced apoptosis. Cell Res 2009; 19: 1363–1376.

    CAS  PubMed  Google Scholar 

  93. Baines CP, Kaiser RA, Sheik T, Craigen WJ, Molkentin JD . Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 2007; 9: 550–555.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Shimizu S, Ide T, Yanagida T, Tsujimoto Y . Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem 2000; 275: 12321–12325.

    CAS  PubMed  Google Scholar 

  95. Arbel N, Ben-Hail D, Shoshan-Barmatz V . Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem 2012; 287: 23152–23161.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Prezma T, Shteinfer A, Admoni L, Raviv Z, Sela I, Levi I, Shoshan-Barmatz V . VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia. Cell Death Dis 2013; 4: e809.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brenner C, Grimm S . The permeability transition pore complex in cancer cell death. Oncogene 2006; 25: 4744–4756.

    CAS  PubMed  Google Scholar 

  98. Bernardi P . The mitochondrial permeability transition pore: a mystery solved? Front Physiol 2013; 4: 95.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Szabó I, Zoratti M . The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 1991; 266: 3376–3379.

    PubMed  Google Scholar 

  100. Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M et al. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 2013; 110: 5887–5892.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rasola A, Sciacovelli M, Pantic B, Bernard P . Signal transduction to the permeability transition pore. FEBS Lett 2010; 584: 1989–1896.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Traba J, Del Arco A, Duchen MR, Szabadkai G, Satrústegui J . SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering. Cell Death Differ 2012; 19: 650–660.

    CAS  PubMed  Google Scholar 

  103. Matassa DS, Amoroso MR, Maddalena F, Landriscina M, Esposito F . New insights into TRAP1 pathway. Am J Cancer Res 2012; 2: 235–248.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Chiara F, Gambalunga A, Sciacovelli M, Nicolli A, Ronconi L, Fregona D et al. Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death. Cell Death Dis 2012; 3: e444.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Elliott MA, Ford SJ, Prasad E, Dick LJ, Farmer H, Hogg PJ et al. Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for Phase I clinical trial. Int J Pharm 2012; 426: 67–75.

    CAS  PubMed  Google Scholar 

  106. Brenner C, Moulin M . Physiological roles of the permeability transition pore. Circ Res 2012; 111: 1237–1247.

    CAS  PubMed  Google Scholar 

  107. Jones S, Martel C, Belzacq-Casagrande AS, Brenner C, Howl J . Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis. Biochim Biophys Acta 2008; 1783: 849–863.

    CAS  PubMed  Google Scholar 

  108. Risso A, Braidot E, Sordano MC, Vianello A, Macrì F, Skerlavaj B et al. BMAP-28, an antibiotic peptide of innate immunity, induces cell death through opening of the mitochondrial permeability transition pore. Mol Cell Biol 2002; 22: 1926–1935.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Horton KL, Pereira MP, Stewart KM, Fonseca SB, Kelley SO . Tuning the activity of mitochondria-penetrating peptides for delivery or disruption. Chembiochem 2012; 13: 476–485.

    CAS  PubMed  Google Scholar 

  110. Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P . Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci USA 2010; 107: 726–731.

    CAS  PubMed  Google Scholar 

  111. Chiara F, Rasola A . GSK-3 and mitochondria in cancer cells. Front Oncol 2013; 3: 16.

    PubMed  PubMed Central  Google Scholar 

  112. Flescher E . Jasmonates—a new family of anti-cancer agents. Anticancer Drugs 2005; 16: 911–916.

    CAS  PubMed  Google Scholar 

  113. Flescher E . Jasmonates in cancer therapy. Cancer Lett 2007; 245: 1–10.

    CAS  PubMed  Google Scholar 

  114. Raviv Z, Cohen S, Reischer-Pelech D . The anti-cancer activities of jasmonates. Cancer Chemother Pharmacol 2013; 71: 275–285.

    CAS  PubMed  Google Scholar 

  115. Lena A, Rechichi M, Salvetti A, Bartoli B, Vecchio D, Scarcelli V et al. Drugs targeting the mitochondrial pore act as cytotoxic and cytostatic agents in temozolomide-resistant glioma cells. J Transl Med 2009; 7: 13.

    PubMed  PubMed Central  Google Scholar 

  116. Javadov S, Hunter JC, Barreto-Torres G, Parodi-Rullan R . Targeting the mitochondrial permeability transition: cardiac ischemia-reperfusion versus carcinogenesis. Cell Physiol Biochem 2011; 27: 179–190.

    CAS  PubMed  Google Scholar 

  117. Pereira GC, Branco AF, Matos JA, Pereira SL, Parke D, Perkins EL et al. Mitochondrially targeted effects of berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. J Pharmacol Exp Ther 2007; 323: 636–649.

    CAS  PubMed  Google Scholar 

  118. Pereira CV, Machado NG, Oliveira PJ . Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocator. Toxicol Sci 2008; 105: 408–417.

    CAS  PubMed  Google Scholar 

  119. Li L, Han W, Gu Y, Qiu S, Lu Q, Jin J et al. Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore. Cancer Res 2007; 67: 4894–4903.

    CAS  PubMed  Google Scholar 

  120. Dong JX, Zhao GY, Yu QL, Li R, Yuan L, Chen J et al. Mitochondrial dysfunction induced by honokiol. J Membr Biol 2013; 246: 375–381.

    CAS  PubMed  Google Scholar 

  121. Cavalieri E, Bergamini C, Mariotto S, Leoni S, Perbellini L, Darra E et al. Involvement of mitochondrial permeability transition pore opening in alpha-bisabolol induced apoptosis. FEBS J 2009; 276: 3990–4000.

    CAS  PubMed  Google Scholar 

  122. Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 2007; 6: 1641–1649.

    CAS  PubMed  Google Scholar 

  123. Broekemeier KM, Dempsey ME, Pfeiffer DR . Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem 1989; 264: 7826–7830.

    CAS  PubMed  Google Scholar 

  124. Crompton M, Ellinger H, Costi A . Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem. J 1988; 255: 357–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fournier N, Ducet G, Crevat A . Action of cyclosporine on mitochondrial calcium fluxes. J Bioenerg Biomembr 1987; 19: 297–303.

    CAS  PubMed  Google Scholar 

  126. Norman KG, Canter JA, Shi M, Milne GL, Morrow JD, Sligh JE . Cyclosporine A suppresses keratinocyte cell death through MMPTP inhibition in a model for skin cancer in organ transplant recipients. Mitochondrion 2010; 10: 94–101.

    CAS  PubMed  Google Scholar 

  127. Szabò I, Bock J, Jekle A, Soddemann M, Adams C, Lang F et al. A novel potassium channel in lymphocyte mitochondria. J Biol Chem 2005; 280: 12790–12798.

    PubMed  Google Scholar 

  128. Gulbins E, Sassi N, Grassmè H, Zoratti M, Szabò I . Role of Kv1.3 mitochondrial potassium channel in apoptotic signalling in lymphocytes. Biochim Biophys Acta 2010; 1797: 1251–1259.

    CAS  PubMed  Google Scholar 

  129. Szabó I, Bock J, Grassmé H, Soddemann M, Wilker B, Lang F et al. Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proc Natl Acad Sci USA 2008; 105: 14861–14866.

    PubMed  PubMed Central  Google Scholar 

  130. Szabò I, Soddemann M, Leanza L, Zoratti M, Gulbins E . Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax- and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosis. Cell Death Differ 2011; 18: 427–438.

    PubMed  Google Scholar 

  131. Annis MG, Soucie EL, Dlugosz PJ, Cruz-Aguado JA, Penn LZ, Leber B et al. Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 24: 2096–2103.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Leanza L, Zoratti M, Gulbins E, Szabò I . Induction of apoptosis in macrophages via Kv1.3 and Kv1.5 potassium channels. Curr Med Chem 2012; 19: 5394–5404.

    CAS  PubMed  Google Scholar 

  133. Leanza L, Henry B, Sassi N, Zoratti M, Chandy KG, Gulbins E et al. Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. EMBO Mol Med 2012; 4: 577–593.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Leanza L, Trentin L, Becker KA, Frezzato F, Zoratti M, Semenzato G et al. Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leukemia 2013; 27: 1782–1785.

    CAS  PubMed  Google Scholar 

  135. Trachootham D, Alexandre J, Huang P . Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 579–591.

    CAS  PubMed  Google Scholar 

  136. Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W et al. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 2003; 278: 37832–37839.

    CAS  PubMed  Google Scholar 

  137. Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J et al. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS One 2008; 3: e4009.

    PubMed  PubMed Central  Google Scholar 

  138. Felipe A, Bielanska J, Comes N, Vallejo A, Roig S, Ramón Y, Cajal S et al. Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention. Curr Med Chem 2012; 19: 661–674.

    CAS  PubMed  Google Scholar 

  139. Leanza L, O’ Reilly P, Doyle A, Venturini E, Zoratti M, Szegezdi E et al. Correlation between potassium channel expression and sensitivity to drug-induced cell death in tumor cell lines. Curr Pharm Des 2013, PMID:23701546.

  140. Liu J, Mu C, Yue W, Li J, Ma B, Zhao L et al. A diterpenoid derivate compound targets selenocysteine of Thioredoxin Reductases and induces Bax/Bak-independent apoptosis. Free Radic Biol Med 2013; 63: 485–494.

    CAS  PubMed  Google Scholar 

  141. Ni B, Ma Q, Li B, Zhao L, Liu Y, Zhu Y, Chen Q . Phenylarsine oxide induces apoptosis in Bax- and Bak-deficient cells through upregulation of Bim. Clin Cancer Res 2012; 18: 140–145.

    CAS  PubMed  Google Scholar 

  142. Lei X, Chen Y, Du G, Yu W, Wang X, Qu H et al. Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in Bcl-2. FASEB J 2006; 20: 2147–2149.

    CAS  PubMed  Google Scholar 

  143. LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P et al. Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 2002; 8: 274–281.

    CAS  PubMed  Google Scholar 

  144. McCurrach ME, Connor TM, Knudson CM, Korsmeyer SJ, Lowe SW . Bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci USA 1997; 94: 2345–2349.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Slöetjes AW, de Witte T et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 1998; 91: 2991–2997.

    CAS  PubMed  Google Scholar 

  146. Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M . Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 2000; 97: 10872–10877.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Sassi N, De Marchi U, Fioretti B, Biasutto L, Gulbins E, Francolini F et al. An investigation of the occurrence and properties of the mitochondrial intermediate conductance Ca2+-activated K+ channel mtKCa3.1. Biochim Biophys Acta Bioenergetics 2010; 1797: 1260–1267.

    CAS  Google Scholar 

  148. Stowe DF, Gadicherla AK, Zhou Y, Aldakkak M, Cheng Q, Kwok WM et al. Protection against cardiac injury by small Ca(2+)-sensitive K(+) channels identified in guinea pig cardiac inner mitochondrial membrane. Biochim Biophys Acta 2013; 1828: 427–442 2013.

    CAS  PubMed  Google Scholar 

  149. Dolga AM, Netter MF, Perocchi F, Doti N, Meissner L, Tobaben S et al. Mitochondrial small conductance SK2 channels prevent glutamate-induced oxytosis and mitochondrial dysfunction. J Biol Chem 2013; 288: 10792–10804.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Singh H, Stefani E, Toro L . Intracellular BK(Ca) (iBK(Ca)) channels. J Physiol 2012; 23: 5937–5947.

    Google Scholar 

  151. Debska-Vielhaber G, Godlewski MM, Kicinska A, Skalska J, Kulawiak B, Piwonska M, Zablocki K, Kunz WS, Szewczyk A, Motyl T . Large-conductance K+ channel openers induce death of human glioma cells. J Physiol Pharmacol 2009; 60: 27–36.

    CAS  PubMed  Google Scholar 

  152. Wrzosek A, Tomaskova Z, Ondrias K, Lukasiak A, Szewczyk A . The potassium channel opener CGS7184 activates Ca2+ release from the endoplasmic reticulum. Eur J Pharmacol 2012; 690: 60–67.

    CAS  PubMed  Google Scholar 

  153. Rusznák Z, Bakondi G, Kosztka L, Pocsai K, Dienes B, Fodor J et al. Mitochondrial expression of the two-pore domain TASK-3 channels in malignantly transformed and non-malignant human cells. Virchows Arch 2008; 452: 415–426.

    PubMed  Google Scholar 

  154. Kovács I, Pocsai K, Czifra G, Sarkadi L, Szu¨cs G, Nemes Z et al. TASK-3 immunoreactivity is present but shows differential distribution in the human gastrointestinal tract. Virchows Arch 2005; 446: 402–410.

    PubMed  Google Scholar 

  155. Kosztka L, Rusznák Z, Nagy D, Nagy Z, Fodor J, Szucs G et al. Inhibition of TASK-3 (KCNK9) channel biosynthesis changes cell morphology and decreases both DNA content and mitochondrial function of melanoma cells maintained in cell culture. Melanoma Res 2011; 21: 308–322.

    CAS  PubMed  Google Scholar 

  156. Toczyłowska-Mamińska R, Olszewska A, Laskowski M, Bednarczyk P, Skowronek K, Szewczyk A . Potassium Channel in the Mitochondria of Human Keratinocytes. J Invest Dermatol 2013, doi:10.1038/jid.2013.422.

    PubMed  Google Scholar 

  157. Lee GW, Park HS, Kim EJ, Cho YW, Kim GT, Mun YJ et al. Reduction of breast cancer cell migration via up-regulation of TASK-3 two-pore domain K+ channel. Acta Physiol 2012; 204: 513–524.

    CAS  Google Scholar 

  158. Innamaa A, Jackson L, Asher V, Van Shalkwyk G, Warren A, Hay D et al. Expression and prognostic significance of the oncogenic K2P potassium channel KCNK9 (TASK-3) in ovarian carcinoma. Anticancer Res 2013; 33: 1401–1408.

    CAS  PubMed  Google Scholar 

  159. Fedorenko A, Lishko PV, Kirichok Y . Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 2012; 151: 400–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Hoang T, Smith MD, Jelokhani-Niaraki M . Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5. Biochemistry 2012; 51: 4004–4014.

    CAS  PubMed  Google Scholar 

  161. Cannon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277–359.

    CAS  PubMed  Google Scholar 

  162. Baffy G . Uncoupling protein-2 and cancer. Mitochondrion 2010; 10: 243–252.

    CAS  PubMed  Google Scholar 

  163. Baffy G, Derdak Z, Robson SC . Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer 2011; 105: 469–474.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J . Uncoupling proteins: a role in protection against reactive oxygen species—or not? Biochim Biophys Acta 2006; 1757: 449–458.

    CAS  PubMed  Google Scholar 

  165. Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000; 26: 435–439.

    CAS  PubMed  Google Scholar 

  166. Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G . The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 2008; 68: 2813–2819.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M . The Warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res 2008; 68: 5198–5205.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K et al. Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PLoS One 2011; 6: e24792.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Sanchez-Alvarez R, Martinez-Outschoorn UE, Lamb R, Hulit J, Howell A, Gandara R et al. Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin. Cell Cycle 2013; 12: 172–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. De Stefani D, Raffaello A, Teardo E, Szabò I, Rizzuto R . A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 2011; 476: 336–340.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 2011; 476: 341–345.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R . The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J 2001; 20: 2690–2701.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Mallilankaraman K, Doonan P, Cárdenas C, Chandramoorthy HC, Müller M, Miller R et al. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 2012; 151: 630–644.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A et al. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 2013; 32: 2362–2376.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, Bonora M et al. Downregulation of the Mitochondrial calcium uniporter by cancer-related miR-25. Curr Biol 2013; 23: 58–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Curry MC, Peters AA, Kenny PA, Roberts-Thomson SJ, Monteith GR . Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 2013; 434: 695–700.

    CAS  PubMed  Google Scholar 

  177. Arvizo RR, Moyano DF, Saha S, Thompson MA, Bhattacharya R, Rotello VM et al. Probing novel roles of the mitochondrial uniporter in ovarian cancer cells using nanoparticles. J Biol Chem 2013; 288: 17610–17618.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Davis FM, Parsonage MT, Cabot PJ, Parat MO, Thompson EW, Roberts-Thomson SJ et al. Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line. Cancer Cell Int 2013; 13: 76.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 2013; 15: 1464–1472.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Sancak Y, Markhard AL, Kitami T, Kovács-Bogdán E, Kamer KJ, Udeshi ND et al. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 2013; 342: 1379–1382.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Chaudhuri D, Sancak Y, Mootha VK, Clapham DE . MCU encodes the pore conducting mitochondrial calcium currents. Elife 2013; 2: e00704.

    PubMed  PubMed Central  Google Scholar 

  182. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 2013; 8: e55785.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Wang YZ, Zeng WZ, Xiao X, Huang Y, Song XL, Yu Z et al. Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death. Cell Death Differ 2013; 20: 1359–1369.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med 2007; 13: 1483–1489.

    CAS  PubMed  Google Scholar 

  185. Ko JH, Ko EA, Gu W, Lim I, Bang H, Zhou T . Expression profiling of ion channel genes predicts clinical outcome in breast cancer. Mol Cancer 2013; 12: 106.

    PubMed  PubMed Central  Google Scholar 

  186. Smith RA, Hartley RC, Murphy MP . Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal 2011; 15: 3021–3038.

    CAS  PubMed  Google Scholar 

  187. Smith RA, Hartley RC, Cochemé HM, Murphy MP . Mitochondrial pharmacology. Trends Pharmacol Sci. 2012; 33: 341–352.

    CAS  PubMed  Google Scholar 

  188. Neuzil J, Dong LF, Rohlena J, Truksa J, Ralph SJ . Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion 2013; 13: 199–208.

    CAS  PubMed  Google Scholar 

  189. Galluzzi LMorselli E, Kepp O, Tajeddine N, Kroemer G . Targeting p53 to mitochondria for cancer therapy. Cell Cycle 2008; 7: 1949–1955.

    Google Scholar 

  190. Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, Debatin KM . Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 1998; 273: 33942–33948.

    CAS  PubMed  Google Scholar 

  191. Cavalieri E, Rigo A, Bonifacio M, Carcereri de Prati A, Guardalben E, Bergamini C, Fato R, Pizzolo G, Suzuki H, Vinante F . Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells. J Transl Med 2011; 9: 45.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Guo XP, Zhang XY, Zhang SD . Clinical trial on the effects of shikonin mixture on later stage lung cancer. Zhong Xi Yi Jie He Za Zhi 1991; 11: 598–599.

    CAS  PubMed  Google Scholar 

  193. Schonherr R . Clinical relevance of ion channels for diagnosis and therapy of cancer. J Membr Biol 2005; 205: 175–184.

    CAS  PubMed  Google Scholar 

  194. Wulff H, Miller MJ, Hansel W, Grissmer S, Cahalan MD, Chandy KG . Design of a potent and selective inhibitor of the intermediate-conductance Ca2+- activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci USA 2000; 97: 8151–8156.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to all co-authors for their important contributions to the work carried out in their laboratories and reported in this review. We apologize for not citing all publications that have been published on this topic. The work carried out in the authors’ laboratories was supported in part by grants from the Italian Association for Cancer Research (AIRC; Grant 11814 to IS), the EMBO Young Investigator Program grant (to IS), the Progetti di Rilevante Interesse Nazionale (PRIN) program (2010CSJX4F to IS and 20107Z8XBW_004 to MZ), the Fondazione Cassa di Risparmio di Padova e Rovigo (to MZ), the CNR Project of Special Interest on Aging (to MZ), the DFG Grant Gu 335/13–3 (to EG), the International Association for Cancer Research (to EG) and the Progetto Giovani Studiosi 2012 (to LL).

Author information

Authors and Affiliations

  1. Department of Biology, University of Padova, Padova, Italy

    L Leanza & I Szabo

  2. CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy

    M Zoratti

  3. Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany

    E Gulbins

Authors
  1. L Leanza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Zoratti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Gulbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Szabo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leanza, L., Zoratti, M., Gulbins, E. et al. Mitochondrial ion channels as oncological targets. Oncogene 33, 5569–5581 (2014). https://doi.org/10.1038/onc.2013.578

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.578

Keywords

This article is cited by

Search

Advanced search

Quick links