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Mitochondria as targets for chemotherapy

  • Cell Death and Disease
  • Published:
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Abstract

Mitochondrial malfunctioning is implicated in the pathogenesis of a variety of disorders, including cancer and multiple neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Disturbance of mitochondrial vital functions, e.g., production of ATP, calcium buffering capacity, and generation of reactive oxygen species, can be potentially involved in disease pathogenesis. Neurological disorders caused by mitochondrial deterioration are often associated with cell loss within specific brain regions. In contrast, mitochondrial alterations in tumor cells and the “Warburg effect” might lead to cell survival and resistance of tumor cells to chemotherapy. This review is devoted to the role of mitochondria in neurodegeneration and tumor formation, and describes how targeting of mitochondria can be beneficial in the therapy of these diseases, which affect a large human population.

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References

  1. Reeve AK, Krishnan KJ, Turnbull DM (2008) Age related mitochondrial degenerative disorders in humans. Biotechnol J 3:750–756. doi:10.1002/biot.200800066

    Article  PubMed  CAS  Google Scholar 

  2. Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12:2263–2280

    Article  PubMed  CAS  Google Scholar 

  3. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906. doi:10.1038/sj.onc.1207521

    Article  PubMed  CAS  Google Scholar 

  4. Lemasters JJ, Qian T, He L, Kim JS, Elmore SP, Cascio WE, Brenner DA (2002) Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy. Antioxid Redox Signal 4:769–781. doi:10.1089/152308602760598918

    Article  PubMed  CAS  Google Scholar 

  5. Moretti L, Yang ES, Kim KW, Lu B (2007) Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat 10:135–143. doi:10.1016/j.drup.2007.05.001

    Article  PubMed  CAS  Google Scholar 

  6. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    PubMed  CAS  Google Scholar 

  7. Kitanaka C, Kuchino Y (1999) Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ 6:508–515. doi:10.1038/sj.cdd.4400526

    Article  PubMed  CAS  Google Scholar 

  8. Morgan MJ, Kim YS, Liu ZG (2008) TNFalpha and reactive oxygen species in necrotic cell death. Cell Res 18:343–349. doi:10.1038/cr.2008.31

    Article  PubMed  CAS  Google Scholar 

  9. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA (2007) AIF-mediated programmed necrosis: a highly regulated way to die. Cell Cycle 6:2612–2619

    PubMed  CAS  Google Scholar 

  10. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15. doi:10.1101/gad.1376506

    Article  PubMed  CAS  Google Scholar 

  11. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119. doi:10.1038/nchembio711

    Article  PubMed  CAS  Google Scholar 

  12. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323. doi:10.1016/j.cell.2008.10.044

    Article  PubMed  CAS  Google Scholar 

  13. Offen D, Elkon H, Melamed E (2000) Apoptosis as a general cell death pathway in neurodegenerative diseases. J Neural Transm Suppl 58:153–166

    PubMed  Google Scholar 

  14. Das A, Guyton MK, Butler JT, Ray SK, Banik NL (2008) Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis. CNS Neurol Disord Drug Targets 7:313–320. doi:10.2174/187152708784936699

    Article  PubMed  CAS  Google Scholar 

  15. Nasir J, Goldberg YP, Hayden MR (1996) Huntington disease: new insights into the relationship between CAG expansion and disease. Hum Mol Genet 5(Spec No):1431–1435

    PubMed  CAS  Google Scholar 

  16. Hackam AS, Yassa AS, Singaraja R, Metzler M, Gutekunst CA, Gan L, Warby S, Wellington CL, Vaillancourt J, Chen N, Gervais FG, Raymond L, Nicholson DW, Hayden MR (2000) Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. J Biol Chem 275:41299–41308. doi:10.1074/jbc.M008408200

    Article  PubMed  CAS  Google Scholar 

  17. Choi SA, Kim SJ, Chung KC (2006) Huntingtin-interacting protein 1-mediated neuronal cell death occurs through intrinsic apoptotic pathways and mitochondrial alterations. FEBS Lett 580:5275–5282. doi:10.1016/j.febslet.2006.08.076

    Article  PubMed  CAS  Google Scholar 

  18. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nunez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 16:3–11. doi:10.1038/cdd.2008.150

    Article  PubMed  CAS  Google Scholar 

  19. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486. doi:10.1084/jem.185.8.1481

    Article  PubMed  CAS  Google Scholar 

  20. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973. doi:10.1016/0896-6273(95)90186-8

    Article  PubMed  CAS  Google Scholar 

  21. Bras M, Queenan B, Susin SA (2005) Programmed cell death via mitochondria: different modes of dying. Biochem (Mosc) 70:231–239. doi:10.1007/s10541-005-0105-4

    Article  CAS  Google Scholar 

  22. Hunter DR, Haworth RA (1979) The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459. doi:10.1016/0003-9861(79)90371-0

    Article  PubMed  CAS  Google Scholar 

  23. Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341(Pt 2):233–249. doi:10.1042/0264-6021:3410233

    Article  PubMed  CAS  Google Scholar 

  24. Crompton M (2000) Mitochondrial intermembrane junctional complexes and their role in cell death. J Physiol 529(Pt 1):11–21. doi:10.1111/j.1469-7793.2000.00011.x

    Article  PubMed  CAS  Google Scholar 

  25. Tsujimoto Y, Ikegaki N, Croce CM (1987) Characterization of the protein product of bcl-2, the gene involved in human follicular lymphoma. Oncogene 2:3–7

    PubMed  CAS  Google Scholar 

  26. Tsujimoto Y, Shimizu S (2000) Bcl-2 family: life-or-death switch. FEBS Lett 466:6–10. doi:10.1016/S0014-5793(99)01761-5

    Article  PubMed  CAS  Google Scholar 

  27. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336. doi:10.1038/348334a0

    Article  PubMed  CAS  Google Scholar 

  28. Hennet T, Bertoni G, Richter C, Peterhans E (1993) Expression of BCL-2 protein enhances the survival of mouse fibrosarcoid cells in tumor necrosis factor-mediated cytotoxicity. Cancer Res 53:1456–1460

    PubMed  CAS  Google Scholar 

  29. Festjens N, van Gurp M, van Loo G, Saelens X, Vandenabeele P (2004) Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol 111:7–27. doi:10.1159/000074483

    Article  PubMed  CAS  Google Scholar 

  30. Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607. doi:10.1038/sj.onc.1207102

    Article  PubMed  CAS  Google Scholar 

  31. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi:10.1126/science.1059108

    Article  PubMed  CAS  Google Scholar 

  32. Abel F, Sjoberg RM, Nilsson S, Kogner P, Martinsson T (2005) Imbalance of the mitochondrial pro- and anti-apoptotic mediators in neuroblastoma tumours with unfavourable biology. Eur J Cancer 41:635–646. doi:10.1016/j.ejca.2004.12.021

    Article  PubMed  CAS  Google Scholar 

  33. Kinnally KW, Antonsson B (2007) A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis 12:857–868. doi:10.1007/s10495-007-0722-z

    Article  PubMed  CAS  Google Scholar 

  34. Pavlov EV, Priault M, Pietkiewicz D, Cheng EH, Antonsson B, Manon S, Korsmeyer SJ, Mannella CA, Kinnally KW (2001) A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J Cell Biol 155:725–731. doi:10.1083/jcb.200107057

    Article  PubMed  CAS  Google Scholar 

  35. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716

    PubMed  CAS  Google Scholar 

  36. Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochem (Mosc) 70:200–214. doi:10.1007/s10541-005-0102-7

    Article  CAS  Google Scholar 

  37. Halestrap AP, Woodfield KY, Connern CP (1997) Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem 272:3346–3354. doi:10.1074/jbc.272.8.4680

    Article  PubMed  CAS  Google Scholar 

  38. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 99:1259–1263. doi:10.1073/pnas.241655498

    Article  PubMed  CAS  Google Scholar 

  39. Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183. doi:10.1146/annurev.pharmtox.47.120505.105122

    Article  PubMed  CAS  Google Scholar 

  40. Fatokun AA, Stone TW, Smith RA (2008) Oxidative stress in neurodegeneration and available means of protection. Front Biosci 13:3288–3311. doi:10.2741/2926

    Article  PubMed  CAS  Google Scholar 

  41. Seaton TA, Cooper JM, Schapira AH (1998) Cyclosporin inhibition of apoptosis induced by mitochondrial complex I toxins. Brain Res 809:12–17. doi:10.1016/S0006-8993(98)00790-2

    Article  PubMed  CAS  Google Scholar 

  42. Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453:49–62

    PubMed  CAS  Google Scholar 

  43. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518. doi:10.1038/nrn2417

    Article  PubMed  CAS  Google Scholar 

  44. Youle RJ, Karbowski M (2005) Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6:657–663. doi:10.1038/nrm1697

    Article  PubMed  CAS  Google Scholar 

  45. Herzig S, Martinou JC (2008) Mitochondrial dynamics: to be in good shape to survive. Curr Mol Med 8:131–137. doi:10.2174/156652408783769625

    Article  PubMed  CAS  Google Scholar 

  46. Amiott EA, Lott P, Soto J, Kang PB, McCaffery JM, DiMauro S, Abel ED, Flanigan KM, Lawson VH, Shaw JM (2008) Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp Neurol 211:115–127. doi:10.1016/j.expneurol.2008.01.010

    Article  PubMed  CAS  Google Scholar 

  47. Detmer SA, Chan DC (2007) Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol 176:405–414. doi:10.1083/jcb.200611080

    Article  PubMed  CAS  Google Scholar 

  48. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. doi:10.1038/nature07534

    Article  PubMed  CAS  Google Scholar 

  49. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166. doi:10.1038/nature04779

    Article  PubMed  CAS  Google Scholar 

  50. Rosen KM, Veereshwarayya V, Moussa CE, Fu Q, Goldberg MS, Schlossmacher MG, Shen J, Querfurth HW (2006) Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells. J Biol Chem 281:12809–12816. doi:10.1074/jbc.M512649200

    Article  PubMed  CAS  Google Scholar 

  51. Muftuoglu M, Elibol B, Dalmizrak O, Ercan A, Kulaksiz G, Ogus H, Dalkara T, Ozer N (2004) Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov Disord 19:544–548. doi:10.1002/mds.10695

    Article  PubMed  Google Scholar 

  52. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100:4078–4083. doi:10.1073/pnas.0737556100

    Article  PubMed  CAS  Google Scholar 

  53. Deng H, Dodson MW, Huang H, Guo M (2008) The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA 105:14503–14508. doi:10.1073/pnas.0803998105

    Article  PubMed  CAS  Google Scholar 

  54. Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D (2007) Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci USA 104:7558–7563. doi:10.1073/pnas.0702228104

    Article  PubMed  CAS  Google Scholar 

  55. Parker WD Jr, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40:1302–1303

    PubMed  Google Scholar 

  56. Cardoso SM, Santana I, Swerdlow RH, Oliveira CR (2004) Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Abeta toxicity. J Neurochem 89:1417–1426. doi:10.1111/j.1471-4159.2004.02438.x

    Article  PubMed  CAS  Google Scholar 

  57. Atamna H, Boyle K (2006) Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer’s disease. Proc Natl Acad Sci USA 103:3381–3386. doi:10.1073/pnas.0600134103

    Article  PubMed  CAS  Google Scholar 

  58. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449. doi:10.1093/hmg/ddl066

    Article  PubMed  CAS  Google Scholar 

  59. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105. doi:10.1038/nm.1868

    Article  PubMed  CAS  Google Scholar 

  60. Naga KK, Sullivan PG, Geddes JW (2007) High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J Neurosci 27:7469–7475. doi:10.1523/JNEUROSCI.0646-07.2007

    Article  PubMed  CAS  Google Scholar 

  61. Eliseev RA, Filippov G, Velos J, VanWinkle B, Goldman A, Rosier RN, Gunter TE (2007) Role of cyclophilin D in the resistance of brain mitochondria to the permeability transition. Neurobiol Aging 28:1532–1542. doi:10.1016/j.neurobiolaging.2006.06.022

    Article  PubMed  CAS  Google Scholar 

  62. Starkov AA, Beal FM (2008) Portal to Alzheimer’s disease. Nat Med 14:1020–1021. doi:10.1038/nm1008-1020

    Article  PubMed  CAS  Google Scholar 

  63. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62. doi:10.1038/362059a0

    Article  PubMed  CAS  Google Scholar 

  64. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775. doi:10.1126/science.8209258

    Article  PubMed  CAS  Google Scholar 

  65. Liu R, Li B, Flanagan SW, Oberley LW, Gozal D, Qiu M (2002) Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival. J Neurochem 80:488–500. doi:10.1046/j.0022-3042.2001.00720.x

    Article  PubMed  CAS  Google Scholar 

  66. Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, Radi R (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28:4115–4122. doi:10.1523/JNEUROSCI.5308-07.2008

    Article  PubMed  CAS  Google Scholar 

  67. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596. doi:10.1074/jbc.M009093200

    Article  PubMed  CAS  Google Scholar 

  68. Antonenko YN, Avetisyan AV, Bakeeva LE, Chernyak BV, Chertkov VA, Domnina LV, Ivanova OY, Izyumov DS, Khailova LS, Klishin SS, Korshunova GA, Lyamzaev KG, Muntyan MS, Nepryakhina OK, Pashkovskaya AA, Pletjushkina OY, Pustovidko AV, Roginsky VA, Rokitskaya TI, Ruuge EK, Saprunova VB, Severina II, Simonyan RA, Skulachev IV, Skulachev MV, Sumbatyan NV, Sviryaeva IV, Tashlitsky VN, Vassiliev JM, Vyssokikh MY, Yaguzhinsky LS, Zamyatnin AA, Zamyatnin AA Jr, Skulachev VP (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochem (Mosc) 73:1273–1287. doi:10.1134/S0006297908120018

    Article  CAS  Google Scholar 

  69. LE Bakeeva, Barskov IV, Egorov MV, Isaev NK, Kapelko VI, Kazachenko AV, Kirpatovsky VI, Kozlovsky SV, Lakomkin VL, Levina SB, Pisarenko OI, Plotnikov EY, Saprunova VB, Serebryakova LI, Skulachev MV, Stelmashook EV, Studneva IM, Tskitishvili OV, Vasilyeva AK, Victorov IV, Zorov DB, Skulachev VP (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke). Biochem (Mosc) 73:1288–1299. doi:10.1134/S000629790812002X

    Article  CAS  Google Scholar 

  70. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH (2004) Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 279:34682–34690. doi:10.1074/jbc.M402999200

    Article  PubMed  CAS  Google Scholar 

  71. Szeto HH (2008) Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 10:601–619. doi:10.1089/ars.2007.1892

    Article  PubMed  CAS  Google Scholar 

  72. Chen H, Wang S, Ding JH, Hu G (2008) Edaravone protects against MPP+-induced cytotoxicity in rat primary cultured astrocytes via inhibition of mitochondrial apoptotic pathway. J Neurochem 106:2345–2352. doi:10.1111/j.1471-4159.2008.05573.x

    Article  PubMed  CAS  Google Scholar 

  73. Kim YJ, Ko HH, Han ES, Lee CS (2007) Lamotrigine inhibition of rotenone- or 1-methyl-4-phenylpyridinium-induced mitochondrial damage and cell death. Brain Res Bull 71:633–640. doi:10.1016/j.brainresbull.2006.12.006

    Article  PubMed  CAS  Google Scholar 

  74. Lee CS, Kim YJ, Ko HH, Han ES (2007) Modulation of 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells by K (ATP) channel block. J Neural Transm 114:297–305. doi:10.1007/s00702-006-0594-3

    Article  PubMed  CAS  Google Scholar 

  75. Frei B, Kim MC, Ames BN (1990) Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA 87:4879–4883. doi:10.1073/pnas.87.12.4879

    Article  PubMed  CAS  Google Scholar 

  76. Sandhu JK, Pandey S, Ribecco-Lutkiewicz M, Monette R, Borowy-Borowski H, Walker PR, Sikorska M (2003) Molecular mechanisms of glutamate neurotoxicity in mixed cultures of NT2-derived neurons and astrocytes: protective effects of coenzyme Q10. J Neurosci Res 72:691–703. doi:10.1002/jnr.10579

    Article  PubMed  CAS  Google Scholar 

  77. Fontaine E, Ichas F, Bernardi P (1998) A ubiquinone-binding site regulates the mitochondrial permeability transition pore. J Biol Chem 273:25734–25740. doi:10.1074/jbc.273.40.25734

    Article  PubMed  CAS  Google Scholar 

  78. Papucci L, Schiavone N, Witort E, Donnini M, Lapucci A, Tempestini A, Formigli L, Zecchi-Orlandini S, Orlandini G, Carella G, Brancato R, Capaccioli S (2003) Coenzyme q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical scavenging property. J Biol Chem 278:28220–28228. doi:10.1074/jbc.M302297200

    Article  PubMed  CAS  Google Scholar 

  79. Naderi J, Somayajulu-Nitu M, Mukerji A, Sharda P, Sikorska M, Borowy-Borowski H, Antonsson B, Pandey S (2006) Water-soluble formulation of coenzyme Q10 inhibits bax-induced destabilization of mitochondria in mammalian cells. Apoptosis 11:1359–1369. doi:10.1007/s10495-006-8417-4

    Article  PubMed  CAS  Google Scholar 

  80. Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB (1994) Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol 36:882–888. doi:10.1002/ana.410360613

    Article  PubMed  CAS  Google Scholar 

  81. Matthews RT, Yang L, Browne S, Baik M, Beal MF (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 95:8892–8897. doi:10.1073/pnas.95.15.8892

    Article  PubMed  CAS  Google Scholar 

  82. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22:1592–1599

    PubMed  CAS  Google Scholar 

  83. Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF (2008) Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer’s disease. J Alzheimers Dis 14:225–234

    PubMed  CAS  Google Scholar 

  84. Cleren C, Yang L, Lorenzo B, Calingasan NY, Schomer A, Sireci A, Wille EJ, Beal MF (2008) Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of parkinsonism. J Neurochem 104:1613–1621. doi:10.1111/j.1471-4159.2007.05097.x

    Article  PubMed  CAS  Google Scholar 

  85. Shults CW (2003) Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 10:1917–1921. doi:10.2174/0929867033456882

    Article  PubMed  CAS  Google Scholar 

  86. Wyss M, Smeitink J, Wevers RA, Wallimann T (1992) Mitochondrial creatine kinase: a key enzyme of aerobic energy metabolism. Biochim Biophys Acta 1102:119–166. doi:10.1016/0005-2728(92)90096-K

    Article  PubMed  CAS  Google Scholar 

  87. Brewer GJ, Wallimann TW (2000) Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem 74:1968–1978. doi:10.1046/j.1471-4159.2000.0741968.x

    Article  PubMed  CAS  Google Scholar 

  88. Andres RH, Ducray AD, Perez-Bouza A, Schlattner U, Huber AW, Krebs SH, Seiler RW, Wallimann T, Widmer HR (2005) Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system. Cell Transplant 14:537–550. doi:10.3727/000000005783982756

    Article  PubMed  Google Scholar 

  89. Brustovetsky N, Brustovetsky T, Dubinsky JM (2001) On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76:425–434. doi:10.1046/j.1471-4159.2001.00052.x

    Article  PubMed  CAS  Google Scholar 

  90. Kira Y, Nishikawa M, Ochi A, Sato E, Inoue M (2006) l-Carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. Brain Res 1070:206–214. doi:10.1016/j.brainres.2005.11.052

    Article  PubMed  CAS  Google Scholar 

  91. Long J, Gao F, Tong L, Cotman CW, Ames BN, Liu J (2008) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and Acetyl-L: -carnitine. Neurochem Res 15(4):685–707

    Google Scholar 

  92. Simonnet H, Alazard N, Pfeiffer K, Gallou C, Beroud C, Demont J, Bouvier R, Schagger H, Godinot C (2002) Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. Carcinogenesis 23:759–768. doi:10.1093/carcin/23.5.759

    Article  PubMed  CAS  Google Scholar 

  93. Halicka HD, Ardelt B, Li X, Melamed MM, Darzynkiewicz Z (1995) 2-Deoxy-d-glucose enhances sensitivity of human histiocytic lymphoma U937 cells to apoptosis induced by tumor necrosis factor. Cancer Res 55:444–449

    PubMed  CAS  Google Scholar 

  94. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 62:3909–3913

    PubMed  CAS  Google Scholar 

  95. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613–621. doi:10.1158/0008-5472.CAN-04-4313

    Article  PubMed  CAS  Google Scholar 

  96. Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, Zheng X, Sadee W, Sun D (2007) Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol 59:495–505. doi:10.1007/s00280-006-0291-9

    Article  PubMed  CAS  Google Scholar 

  97. Lopez-Lazaro M (2007) Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 11:1043–1053. doi:10.1517/14728222.11.8.1043

    Article  PubMed  CAS  Google Scholar 

  98. Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, Zamzami N, Xie Z, Reed J, Kroemer G (1999) Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 249:413–421. doi:10.1006/excr.1999.4519

    Article  PubMed  CAS  Google Scholar 

  99. Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2000) Distinct pathways for stimulation of cytochrome c release by etoposide. J Biol Chem 275:32438–32443. doi:10.1074/jbc.C000518200

    Article  PubMed  CAS  Google Scholar 

  100. Pastorino JG, Hoek JB (2008) Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr 40:171–182. doi:10.1007/s10863-008-9148-8

    Article  PubMed  CAS  Google Scholar 

  101. Haridas V, Li X, Mizumachi T, Higuchi M, Lemeshko VV, Colombini M, Gutterman JU (2007) Avicins, a novel plant-derived metabolite lowers energy metabolism in tumor cells by targeting the outer mitochondrial membrane. Mitochondrion 7:234–240. doi:10.1016/j.mito.2006.12.005

    Article  PubMed  CAS  Google Scholar 

  102. Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V (2008) Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem 283:13482–13490. doi:10.1074/jbc.M708216200

    Article  PubMed  CAS  Google Scholar 

  103. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681. doi:10.1038/nature03579

    Article  PubMed  CAS  Google Scholar 

  104. Huang S, Sinicrope FA (2008) BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res 68:2944–2951. doi:10.1158/0008-5472.CAN-07-2508

    Article  PubMed  CAS  Google Scholar 

  105. Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned TM, Lock RB, Reynolds CP (2007) Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood 110:2057–2066. doi:10.1182/blood-2007-03-080325

    Article  PubMed  CAS  Google Scholar 

  106. Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Murotani Y, Matsumoto Y, Tanaka H, Strasser A, Taniwaki M, Maekawa T (2008) ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol 140:181–190

    PubMed  CAS  Google Scholar 

  107. Vogler M, Dinsdale D, Sun XM, Young KW, Butterworth M, Nicotera P, Dyer MJ, Cohen GM (2008) A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells. Cell Death Differ 15:820–830. doi:10.1038/cdd.2008.25

    Article  PubMed  CAS  Google Scholar 

  108. Gogvadze V, Robertson JD, Zhivotovsky B, Orrenius S (2001) Cytochrome c release occurs via Ca2+-dependent and Ca2+-independent mechanisms that are regulated by Bax. J Biol Chem 276:19066–19071. doi:10.1074/jbc.M100614200

    Article  PubMed  CAS  Google Scholar 

  109. Vogler M, Dinsdale D, Dyer MJ, Cohen GM (2008) Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ

  110. Ponassi R, Biasotti B, Tomati V, Bruno S, Poggi A, Malacarne D, Cimoli G, Salis A, Pozzi S, Miglino M, Damonte G, Cozzini P, Spyraki F, Campanini B, Bagnasco L, Castagnino N, Tortolina L, Mumot A, Frassoni F, Daga A, Cilli M, Piccardi F, Monfardini I, Perugini M, Zoppoli G, D’Arrigo C, Pesenti R, Parodi S (2008) A novel Bim-BH3-derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity. Cell Cycle 7:3211–3224

    PubMed  CAS  Google Scholar 

  111. Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J, Zhang KY, Hockenbery DM (2001) Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 3:183–191. doi:10.1038/35055095

    Article  PubMed  CAS  Google Scholar 

  112. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, Croce CM, Alnemri ES, Huang Z (2000) Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 97:7124–7129. doi:10.1073/pnas.97.13.7124

    Article  PubMed  CAS  Google Scholar 

  113. Campas C, Cosialls AM, Barragan M, Iglesias-Serret D, Santidrian AF, Coll-Mulet L, de Frias M, Domingo A, Pons G, Gil J (2006) Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol 34:1663–1669. doi:10.1016/j.exphem.2006.07.008

    Article  PubMed  CAS  Google Scholar 

  114. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51. doi:10.1016/j.ccr.2006.10.020

    Article  PubMed  CAS  Google Scholar 

  115. Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A (2007) Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res 67:1602–1608. doi:10.1158/0008-5472.CAN-06-2870

    Article  PubMed  CAS  Google Scholar 

  116. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434. doi:10.1016/j.ccr.2006.04.023

    Article  PubMed  CAS  Google Scholar 

  117. Beckers A, Organe S, Timmermans L, Scheys K, Peeters A, Brusselmans K, Verhoeven G, Swinnen JV (2007) Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res 67:8180–8187. doi:10.1158/0008-5472.CAN-07-0389

    Article  PubMed  CAS  Google Scholar 

  118. MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E (2007) Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 27:3282–3289. doi:10.1128/MCB.01927-06

    Article  PubMed  CAS  Google Scholar 

  119. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055. doi:10.1158/0008-5472.CAN-05-1235

    Article  PubMed  CAS  Google Scholar 

  120. Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, Dang CV (2007) HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238. doi:10.1016/j.ccr.2007.08.004

    Article  PubMed  CAS  Google Scholar 

  121. Brizel DM, Esclamado R (2006) Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum. J Clin Oncol 24:2612–2617. doi:10.1200/JCO.2005.05.2829

    Article  PubMed  Google Scholar 

  122. Chi SL, Wahl ML, Mowery YM, Shan S, Mukhopadhyay S, Hilderbrand SC, Kenan DJ, Lipes BD, Johnson CE, Marusich MF, Capaldi RA, Dewhirst MW, Pizzo SV (2007) Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase. Cancer Res 67:4716–4724. doi:10.1158/0008-5472.CAN-06-1094

    Article  PubMed  CAS  Google Scholar 

  123. Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, Wolff K, Eichler HG, Pehamberger H (1998) Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 4:232–234. doi:10.1038/nm0298-232

    Article  PubMed  CAS  Google Scholar 

  124. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466–1470. doi:10.1126/science.1099191

    Article  PubMed  CAS  Google Scholar 

  125. Ravagnan L, Marzo I, Costantini P, Susin SA, Zamzami N, Petit PX, Hirsch F, Goulbern M, Poupon MF, Miccoli L, Xie Z, Reed JC, Kroemer G (1999) Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 18:2537–2546. doi:10.1038/sj.onc.1202625

    Article  PubMed  CAS  Google Scholar 

  126. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W (2000) Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407:390–395. doi:10.1038/35030140

    Article  PubMed  CAS  Google Scholar 

  127. Neuzil J, Weber T, Gellert N, Weber C (2001) Selective cancer cell killing by alpha-tocopheryl succinate. Br J Cancer 84:87–89. doi:10.1054/bjoc.2000.1559

    Article  PubMed  CAS  Google Scholar 

  128. Shen J, Vakifahmetoglu H, Stridh H, Zhivotovsky B, Wiman KG (2008) PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene 27:6571–6580. doi:10.1038/onc.2008.249

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Work in the authors’ laboratory was supported by grants from The Swedish and Stockholm Cancer Societies, The Swedish Childhood Cancer Foundation, The Swedish Research Council, the EC-FP-6 (Oncodeath and Chemores) and EC-FP-7 (APO-SYS). We apologize to authors whose primary references could not be cited owing to space limitations.

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  1. Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, P.O. Box 210, 171 77, Stockholm, Sweden

    Vladimir Gogvadze, Sten Orrenius & Boris Zhivotovsky

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  1. Vladimir Gogvadze
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  2. Sten Orrenius
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Correspondence to Vladimir Gogvadze.

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Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria as targets for chemotherapy. Apoptosis 14, 624–640 (2009). https://doi.org/10.1007/s10495-009-0323-0

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