InTech uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Engineering » Biomedical Engineering » "Biosensors for Health, Environment and Biosecurity", book edited by Pier Andrea Serra, ISBN 978-953-307-443-6, Published: July 19, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 19

Mitochondria as a Biosensor for Drug-induced Toxicity – Is It Really Relevant?

By Oliveira, Ana Moreira, Nuno Machado, Telma Bernardo and Vilma Sardao
DOI: 10.5772/17805

  1. V. Adam-Vizi, C. Chinopoulos, 2006 Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27. 12 639 45 .

  2. M. Ahmed, S. J. Muhammed, B. Kessler, A. Salehi, 2011 Mitochondrial proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic beta-cells exposed to high glucose. Islets 2. 5 283 92 .

  3. I. Ak, M. P. Stokkel, E. K. Pauwels, 2000 Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose in oncology. Part II. The clinical value in detecting and staging primary tumours. J Cancer Res Clin Oncol 126. 10 560 74 .

  4. H. A. Aly, O. Domenech, 2009 Cytotoxicity and mitochondrial dysfunction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in isolated rat hepatocytes. Toxicol Lett 191. 1 79 87 .

  5. S. Amaral, P. C. Mota, B. Lacerda, M. Alves, Mde. L. Pereira, P. J. Oliveira, J. Ramalho-Santos, 2009 Testicular mitochondrial alterations in untreated streptozotocin-induced diabetic rats. Mitochondrion 9. 1 41 50 .

  6. S. Amaral, P. J. Oliveira, J. Ramalho-Santos, 2008 Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 4. 1 46 54 .

  7. D. Arnoult, 2007 Mitochondrial fragmentation in apoptosis. Trends Cell Biol 17. 1 6 12 .

  8. D. Arnoult, A. Grodet, Y. J. Lee, J. Estaquier, C. Blackstone, 2005 Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation. J Biol Chem 280. 42 35742 50 .

  9. O. J. Arola, A. Saraste, K. Pulkki, M. Kallajoki, M. Parvinen, L. M. Voipio-Pulkki, 2000 Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60. 7 1789 92 .

  10. A. Ascensao, J. Lumini-Oliveira, N. G. Machado, R. M. Ferreira, I. O. Goncalves, A. C. Moreira, F. Marques, V. A. Sardao, P. J. Oliveira, J. Magalhaes, Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats. Clin Sci (Lond) 120 1 37 49 .

  11. R. S. Balaban, S. Nemoto, T. Finkel, 2005 Mitochondria, oxidants, and aging. Cell 120. 4 483 95 .

  12. M. Barile, D. Valenti, G. A. Hobbs, M. F. Abruzzese, S. A. Keilbaugh, S. Passarella, E. Quagliariello, M. V. Simpson, 1994 Mechanisms of toxicity of 3’-azido-3’-deoxythymidine. Its interaction with adenylate kinase. Biochem Pharmacol 48. 7 1405 12 .

  13. M. Barile, D. Valenti, S. Passarella, E. Quagliariello, 1997 3’-Azido-3’-deoxythmidine uptake into isolated rat liver mitochondria and impairment of ADP/ATP translocator. Biochem Pharmacol 53. 7 913 20 .

  14. A. Barrientos, F. Fontanesi, F. Diaz, 2009 Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. Curr Protoc Hum Genet Chapter 19. Unit19 EOF 3.

  15. P. J. Barter, K. A. Rye, 2006 Cardioprotective properties of fibrates: which fibrate, which patients, what mechanism? Circulation 113. 12 1553 5 .

  16. C. C. Beeson, G. C. Beeson, R. G. Schnellmann, 2010 A high-throughput respirometric assay for mitochondrial biogenesis and toxicity. Anal Biochem 404. 1 75 81 .

  17. N. Bellance, P. Lestienne, R. Rossignol, 2009 Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis. Front Biosci 14. 4015 34 .

  18. E. A. Belyaeva, D. Dymkowska, M. R. Wieckowski, L. Wojtczak, 2008 Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. Toxicol Appl Pharmacol 231. 1 34 42 .

  19. E. A. Belyaeva, V. V. Glazunov, S. M. Korotkov, 2004 Cd2+-promoted mitochondrial permeability transition: a comparison with other heavy metals. Acta Biochim Pol 51. 2 545 51 .

  20. M. Berneburg, Y. Kamenisch, J. Krutmann, M. Rocken, 2006 ‘To repair or not to repair- no longer a question’: repair of mitochondrial DNA shielding against age and cancer. Exp Dermatol 15. 12 1005 15 .

  21. J. M. Berthiaume, P. J. Oliveira, M. W. Fariss, K. B. Wallace, 2005 Dietary vitamin E decreases doxorubicin-induced oxidative stress without preventing mitochondrial dysfunction. Cardiovasc Toxicol 5. 3 257 67 .

  22. J. M. Berthiaume, K. B. Wallace, 2007 Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 23. 1 15 25 .

  23. J. M. Berthiaume, K. B. Wallace, 2007 Persistent alterations to the gene expression profile of the heart subsequent to chronic Doxorubicin treatment. Cardiovasc Toxicol 7. 3 178 91 .

  24. G. Biswas, S. Srinivasan, H. K. Anandatheerthavarada, N. G. Avadhani, 2008 Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling. Proc Natl Acad Sci U S A 105. 1 186 91 .

  25. L. M. Blanco-Colio, P. Justo, I. Daehn, C. Lorz, A. Ortiz, J. Egido, 2003 Bcl-xL overexpression protects from apoptosis induced by HMG-CoA reductase inhibitors in murine tubular cells. Kidney Int 64. 1 181 91 .

  26. H. L. Bonkovsky, R. W. Lambrecht, 2000 Iron-induced liver injury. Clin Liver Dis 4. 2 409 29 , vi-vii.

  27. M. P. Bova, D. Tam, G. Mc Mahon, M. N. Mattson, 2005 Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells. Toxicol Lett 155. 1 41 50 .

  28. E. Boyland, M. E. Boyland, 1936 Studies in tissue metabolism: The effect of fumarate and succinate on tumour respiration. Biochem J 30. 2 224 6 .

  29. M. Brandon, P. Baldi, D. C. Wallace, 2006 Mitochondrial mutations in cancer. Oncogene 25. 34 4647 62 .

  30. M. R. Bristow, W. A. Minobe, M. E. Billingham, J. B. Marmor, G. A. Johnson, B. M. Ishimoto, W. S. Sageman, J. R. Daniels, 1981 Anthracycline-associated cardiac and renal damage in rabbits. Evidence for mediation by vasoactive substances. Lab Invest 45. 2 157 68 .

  31. G. C. Brown, V. Borutaite, 2007 Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 75. 2 283 90 .

  32. B. Brunmair, A. Lest, K. Staniek, F. Gras, N. Scharf, M. Roden, H. Nohl, W. Waldhausl, C. Furnsinn, 2004 Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I. J Pharmacol Exp Ther 311. 1 109 14 .

  33. B. Brunmair, K. Staniek, F. Gras, N. Scharf, A. Althaym, R. Clara, M. Roden, E. Gnaiger, H. Nohl, W. Waldhausl, C. Furnsinn, 2004 Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53. 4 1052 9 .

  34. H. Bugger, E. D. Abel, 2011 Mitochondria in the diabetic heart. Cardiovasc Res 88. 2 229 40 .

  35. H. Bugger, C. Guzman, C. Zechner, M. Palmeri, K. S. Russell, R. Russell, 3 3rd. Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation. Cancer Chemother Pharmacol.

  36. E. Cadenas, 2004 Mitochondrial free radical production and cell signaling. Mol Aspects Med 25. 1-2: 17-26.

  37. P. Cafforio, F. Dammacco, A. Gernone, F. Silvestris, 2005 Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 26. 5 883 91 .

  38. G. Cannino, E. Ferruggia, C. Luparello, A. M. Rinaldi, 2009 Cadmium and mitochondria. Mitochondrion 9. 6 377 84 .

  39. P. Carranza-Rosales, S. Said-Fernandez, J. Sepulveda-Saavedra, D. E. Cruz-Vega, A. J. Gandolfi, 2005 Morphologic and functional alterations induced by low doses of mercuric chloride in the kidney OK cell line: ultrastructural evidence for an apoptotic mechanism of damage. Toxicology 210. 2-3: 111-21.

  40. K. Chan, D. Truong, N. Shangari, P. J. O’Brien, 2005 Drug-induced mitochondrial toxicity. Expert Opin Drug Metab Toxicol 1. 4 655 69 .

  41. D. Chandra, K. K. Singh, 2010 Genetic insights into OXPHOS defect and its role in cancer. Biochim Biophys Acta.

  42. B. Chen, X. Peng, L. Pentassuglia, C. C. Lim, D. B. Sawyer, 2007 Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol 7. 2 114 21 .

  43. P. Cole, D. Trichopoulos, H. Pastides, T. Starr, J. S. Mandel, 2003 Dioxin and cancer: a critical review. Regul Toxicol Pharmacol 38. 3 378 88 .

  44. B. S. Connolly, A. S. Feigenbaum, B. H. Robinson, A. I. Dipchand, D. K. Simon, M. A. Tarnopolsky, 2010 MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation. Biochem Biophys Res Commun 402. 2 443 7 .

  45. F. Cornelio, S. Di Donato, 1985 Myopathies due to enzyme deficiencies. J Neurol 232. 6 329 40 .

  46. S. Correia, C. Carvalho, M. S. Santos, R. Seica, C. R. Oliveira, P. I. Moreira, 2008 Mechanisms of action of metformin in type 2 diabetes and associated complications: an overview. Mini Rev Med Chem 8. 13 1343 54 .

  47. C. Curti, F. E. Mingatto, A. C. Polizello, L. O. Galastri, S. A. Uyemura, A. C. Santos, 1999 Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0 -ATPase activity. Mol Cell Biochem 199. 1-2: 103-9.

  48. M. H. Davidson, 2001 Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust. Drugs 61. 2 197 206 .

  49. K. J. Davies, J. H. Doroshow, 1986 Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem 261. 7 3060 7 .

  50. R. Davis, R. Whittington, H. M. Bryson, 1997 Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 53. 4 608 36 .

  51. P. B. de Andrade, B. Rubi, F. Frigerio, Ouweland. J. M. van den, J. A. Maassen, P. Maechler, 2006 Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function. Diabetologia 49. 8 1816 26 .

  52. J. G. de la Asuncion, M. L. Del Olmo, L. G. Gomez-Cambronero, J. Sastre, F. V. Pallardo, J. Vina, 2004 AZT induces oxidative damage to cardiac mitochondria: protective effect of vitamins C and E. Life Sci 76. 1 47 56 .

  53. T. E. Delea, J. S. Edelsberg, M. Hagiwara, G. Oster, L. S. Phillips, 2003 Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 26. 11 2983 9 .

  54. S. A. Detmer, D. C. Chan, 2007 Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8. 11 870 9 .

  55. F. Diaz, A. Barrientos, F. Fontanesi, 2009 Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using blue native gel electrophoresis. Curr Protoc Hum Genet Chapter 19. Unit19 4.

  56. S. Dimauro, G. Davidzon, 2005 Mitochondrial DNA and disease. Ann Med 37. 3 222 32 .

  57. J. H. Doroshow, K. J. Davies, 1986 Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem 261. 7 3068 74 .

  58. J. A. Dykens, J. D. Jamieson, L. D. Marroquin, S. Nadanaciva, J. J. Xu, M. C. Dunn, A. R. Smith, Y. Will, 2008 In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 103. 2 335 45 .

  59. J. A. Dykens, L. D. Marroquin, Y. Will, 2007 Strategies to reduce late-stage drug attrition due to mitochondrial toxicity. Expert Rev Mol Diagn 7. 2 161 75 .

  60. M. Y. El -Mir, V. Nogueira, E. Fontaine, N. Averet, M. Rigoulet, X. Leverve, 2000 Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275. 1 223 8 .

  61. V. L. Ellingrod, P. J. Perry, 1995 Nefazodone: a new antidepressant. Am J Health Syst Pharm 52. 24 2799 812 .

  62. F. M. Ferreira, C. M. Palmeira, R. Seica, A. J. Moreno, M. S. Santos, 2003 Diabetes and mitochondrial bioenergetics: alterations with age. J Biochem Mol Toxicol 17. 4 214 22 .

  63. F. M. Ferreira, R. Seica, P. J. Oliveira, P. M. Coxito, A. J. Moreno, C. M. Palmeira, M. S. Santos, 2003 Diabetes induces metabolic adaptations in rat liver mitochondria: role of coenzyme Q and cardiolipin contents. Biochim Biophys Acta 1639. 2 113 20 .

  64. K. Folkers, P. Langsjoen, R. Willis, P. Richardson, L. J. Xia, C. Q. Ye, H. Tamagawa, 1990 Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 87. 22 8931 4 .

  65. B. Fromenty, E. Freneaux, G. Labbe, D. Deschamps, D. Larrey, P. Letteron, D. Pessayre, 1989 Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice. Biochem Pharmacol 38. 21 3743 51 .

  66. J. P. Fruehauf, F. L. Meyskens, Jr , 2007 Reactive oxygen species: a breath of life or death? Clin Cancer Res 13. 3 789 94 .

  67. H. Fujimori, K. Ozaki, T. Matsuura, S. Matsushima, I. Narama, H. Pan-Hou, 2004 Effect of iron lactate overloading on adenine nucleotide levels and adenosine 3’-monophosphate forming enzyme in rat liver and spleen. Biol Pharm Bull 27. 9 1371 5 .

  68. L. Galluzzi, M. C. Maiuri, I. Vitale, H. Zischka, M. Castedo, L. Zitvogel, G. Kroemer, 2007 Cell death modalities: classification and pathophysiological implications. Cell Death Differ 14. 7 1237 43 .

  69. G. Gobe, D. Crane, 2011 Mitochondria, reactive oxygen species and cadmium toxicity in the kidney. Toxicol Lett 198. 1 49 55 .

  70. S. Grandemange, S. Herzig, J. C. Martinou, 2009 Mitochondrial dynamics and cancer. Semin Cancer Biol 19. 1 50 6 .

  71. B. B. Hasinoff, K. L. Schnabl, R. A. Marusak, D. Patel, E. Huebner, 2003 Dexrazoxane (ICRF-187) protects cardiac myocytes against doxorubicin by preventing damage to mitochondria. Cardiovasc Toxicol 3. 2 89 99 .

  72. S. L. Hebert, I. R. Lanza, K. S. Nair, 2010 Mitochondrial DNA alterations and reduced mitochondrial function in aging. Mech Ageing Dev 131. 7-8: 451-62.

  73. C. Hershko, 2011 Pathogenesis and management of iron toxicity in thalassemia. Ann N Y Acad Sci 1202. 1 9 .

  74. M. S. Horenstein, Heide. R. S. Vander, T. J. L’Ecuyer, 2000 Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Mol Genet Metab 71. 1-2: 436-44.

  75. S. Hossain, H. N. Liu, M. Nguyen, G. Shore, G. Almazan, 2009 Cadmium exposure induces mitochondria-dependent apoptosis in oligodendrocytes. Neurotoxicology 30. 4 544 54 .

  76. R. Hrdina, V. Gersl, I. Klimtova, T. Simunek, J. Machackova, M. Adamcova, 2000 Anthracycline-induced cardiotoxicity. Acta Medica (Hradec Kralove) 43. 3 75 82 .

  77. R. S. Hundal, M. Krssak, S. Dufour, D. Laurent, V. Lebon, V. Chandramouli, S. E. Inzucchi, W. C. Schumann, K. F. Petersen, B. R. Landau, G. I. Shulman, 2000 Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49. 12 2063 9 .

  78. W. Y. Hung, C. W. Wu, P. H. Yin, C. J. Chang, A. F. Li, C. W. Chi, Y. H. Wei, H. C. Lee, 2010 Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim Biophys Acta 1800. 3 264 70 .

  79. J. Hynes, L. D. Marroquin, V. I. Ogurtsov, K. N. Christiansen, G. J. Stevens, D. B. Papkovsky, Y. Will, 2006 Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol Sci 92. 1 186 200 .

  80. T. Iwasaki, T. Suzuki, 1991 Ultrastructural alterations of the myocardium induced by doxorubicin. A scanning electron microscopic study. Virchows Arch B Cell Pathol Incl Mol Pathol 60. 1 35 9 .

  81. S. Jenkins, C. Rowell, J. Wang, C. A. Lamartiniere, 2007 Prenatal TCDD exposure predisposes for mammary cancer in rats. Reprod Toxicol 23. 3 391 6 .

  82. S. Y. Jeong, D. W. Seol, 2008 The role of mitochondria in apoptosis. BMB Rep 41. 1 11 22 .

  83. P. Jezek, L. Plecita-Hlavata, 2009 Mitochondrial reticulum network dynamics in relation to oxidative stress, redox regulation, and hypoxia. Int J Biochem Cell Biol 41. 10 1790 804 .

  84. S. Jitrapakdee, A. Wutthisathapornchai, J. C. Wallace, Donald. M. J. Mac, 2011 Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia 53. 6 1019 32 .

  85. J. D. Johnson, D. S. Luciani, 2011 Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies. Adv Exp Med Biol 654. 447 62 .

  86. A. I. Jonckheere, M. Huigsloot, A. J. Janssen, A. J. Kappen, J. A. Smeitink, R. J. Rodenburg, 2010 High-throughput assay to measure oxygen consumption in digitonin-permeabilized cells of patients with mitochondrial disorders. Clin Chem 56. 3 424 31 .

  87. A. Jourdain, J. C. Martinou, 2009 Mitochondrial outer-membrane permeabilization and remodelling in apoptosis. Int J Biochem Cell Biol 41. 10 1884 9 .

  88. K. Jung, R. Reszka, 2001 Mitochondria as subcellular targets for clinically useful anthracyclines. Adv Drug Deliv Rev 49. 1-2: 87-105.

  89. A. J. Karter, A. T. Ahmed, J. Liu, H. H. Moffet, M. M. Parker, A. Ferrara, J. V. Selby, 2004 Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study: response to Delea et al. Diabetes Care 27. 3 850 1 ; author reply 852-3.

  90. P. Kaufmann, M. Torok, A. Zahno, K. M. Waldhauser, K. Brecht, S. Krahenbuhl, 2006 Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol Life Sci 63. 19-20: 2415-25.

  91. J. F. Kerr, A. H. Wyllie, A. R. Currie, 1972 Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26. 4 239 57 .

  92. S. A. Kliewer, H. E. Xu, M. H. Lambert, T. M. Willson, 2001 Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res 56. 239 63 .

  93. S. Knerr, D. Schrenk, 2006 Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Mol Nutr Food Res 50. 10 897 907 .

  94. D. Kobayashi, S. Ahmed, M. Ishida, S. Kasai, H. Kikuchi, 2009 Calcium/calmodulin signaling elicits release of cytochrome c during 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced apoptosis in the human lymphoblastic T-cell line, L-MAT. Toxicology 258. 1 25 32 .

  95. R. A. Kowluru, L. Atasi, Y. S. Ho, 2006 Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 47. 4 1594 9 .

  96. G. Krumschnabel, C. Manzl, C. Berger, B. Hofer, 2005 Oxidative stress, mitochondrial permeability transition, and cell death in Cu-exposed trout hepatocytes. Toxicol Appl Pharmacol 209. 1 62 73 .

  97. J. Kucharska, Z. Braunova, O. Ulicna, L. Zlatos, A. Gvozdjakova, 2000 Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol Res 49. 4 411 8 .

  98. T. L’Ecuyer, S. Sanjeev, R. Thomas, R. Novak, L. Das, W. Campbell, R. V. Heide, 2006 DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol 291. 3: H1273 80 .

  99. M. H. Lader, 1996 Tolerability and safety: essentials in antidepressant pharmacotherapy. J Clin Psychiatry 57 Suppl 2. 39 44 .

  100. C. Latchoumycandane, K. C. Chitra, P. P. Mathur, 2002 The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antioxidant system in mitochondrial and microsomal fractions of rat testis. Toxicology 171. 2-3: 127-35.

  101. D. Lebrecht, J. Kirschner, A. Geist, J. Haberstroh, U. A. Walker, Respiratory chain deficiency precedes the disrupted calcium homeostasis in chronic doxorubicin cardiomyopathy. Cardiovasc Pathol 195 5: e167 74 .

  102. H. C. Lee, C. M. Chang, C. W. Chi, 2010 Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 9 Suppl 1. S47 58 .

  103. E. A. Lefrak, J. Pitha, S. Rosenheim, J. A. Gottlieb, 1973 A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32. 2 302 14 .

  104. W. Lewis, J. J. Kohler, S. H. Hosseini, C. P. Haase, W. C. Copeland, R. J. Bienstock, T. Ludaway, J. Mc Naught, R. Russ, T. Stuart, R. Santoianni, 2006 Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. AIDS 20. 5 675 84 .

  105. W. Lewis, J. F. Simpson, R. R. Meyer, 1994 Cardiac mitochondrial DNA polymerase-gamma is inhibited competitively and noncompetitively by phosphorylated zidovudine. Circ Res 74. 2 344 8 .

  106. N. Li, K. Ragheb, G. Lawler, J. Sturgis, B. Rajwa, J. A. Melendez, J. P. Robinson, 2003 Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278. 10 8516 25 .

  107. L. P. Liang, M. Patel, 2004 Iron-sulfur enzyme mediated mitochondrial superoxide toxicity in experimental Parkinson’s disease. J Neurochem 90. 5 1076 84 .

  108. P. L. Lim, J. Liu, M. L. Go, U. A. Boelsterli, 2008 The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci 101. 2 341 9 .

  109. S. Liu, T. Okada, A. Assmann, J. Soto, C. W. Liew, H. Bugger, O. S. Shirihai, E. D. Abel, R. N. Kulkarni, 2009 Insulin signaling regulates mitochondrial function in pancreatic beta-cells. PLoS One 4. 11: e7983.

  110. H. Lu, V. Koshkin, E. M. Allister, A. V. Gyulkhandanyan, M. B. Wheeler, 2011 Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes 59. 2 448 59 .

  111. M. I. Lucena, E. Garcia-Martin, R. J. Andrade, C. Martinez, C. Stephens, J. D. Ruiz, E. Ulzurrun, M. C. Fernandez, M. Romero-Gomez, A. Castiella, R. Planas, J. A. Duran, A. M. De Dios, C. Guarner, G. Soriano, Y. Borraz, J. A. Agundez, Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 521 1 303 12 .

  112. K. C. Lund, K. B. Wallace, 2004 Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics. Cardiovasc Toxicol 4. 3 217 28 .

  113. K. C. Lund, K. B. Wallace, 2008 Adenosine 3’,5’-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors. Toxicol Appl Pharmacol 226. 1 94 106 .

  114. M. D. Lynx, A. T. Bentley, E. E. Mc Kee, 2006 3’-Azido-3’-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: a possible mechanism of AZT hepatotoxicity. Biochem Pharmacol 71. 9 1342 8 .

  115. M. D. Lynx, E. E. Mc Kee, 2006 3’-Azido-3’-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria. Biochem Pharmacol 72. 2 239 43 .

  116. P. Maechler, N. Li, M. Casimir, L. Vetterli, F. Frigerio, T. Brun, 2011 Role of mitochondria in beta-cell function and dysfunction. Adv Exp Med Biol 654. 193 216 .

  117. F. Malka, O. Guillery, C. Cifuentes-Diaz, E. Guillou, P. Belenguer, A. Lombes, M. Rojo, 2005 Separate fusion of outer and inner mitochondrial membranes. EMBO Rep 6. 9 853 9 .

  118. F. Malka, A. Lombes, M. Rojo, 2006 Organization, dynamics and transmission of mitochondrial DNA: focus on vertebrate nucleoids. Biochim Biophys Acta 1763. 5-6: 463-72.

  119. O. Marcillat, Y. Zhang, K. J. Davies, 1989 Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin. Biochem J 259. 1 181 9 .

  120. A. Marin-Hernandez, J. C. Gallardo-Perez, S. J. Ralph, S. Rodriguez-Enriquez, R. Moreno-Sanchez, 2009 HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 9. 9 1084 101 .

  121. D. N. Martin, E. H. Baehrecke, 2004 Caspases function in autophagic programmed cell death in Drosophila. Development 131. 2 275 84 .

  122. J. C. Martinou, D. R. Green, 2001 Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2. 1 63 7 .

  123. R. Mc Farland, R. W. Taylor, D. M. Turnbull, 2002 The neurology of mitochondrial DNA disease. Lancet Neurol 1. 6 343 51 .

  124. N. Mezghani, E. Mkaouar-Rebai, M. Mnif, N. Charfi, N. Rekik, S. Youssef, M. Abid, F. Fakhfakh, 2011 The heteroplasmic m.14709T>C mutation in the tRNA(Glu) gene in two Tunisian families with mitochondrial diabetes. J Diabetes Complications 24. 4 270 7 .

  125. E. G. Mimnaugh, M. A. Trush, M. Bhatnagar, T. E. Gram, 1985 Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin. Biochem Pharmacol 34. 6 847 56 .

  126. G. Minotti, S. Recalcati, P. Menna, E. Salvatorelli, G. Corna, G. Cairo, 2004 Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent and independent mechanisms. Methods Enzymol 378. 340 61 .

  127. P. I. Moreira, M. S. Santos, A. M. Moreno, T. Proenca, R. Seica, C. R. Oliveira, 2004 Effect of streptozotocin-induced diabetes on rat brain mitochondria. J Neuroendocrinol 16. 1 32 8 .

  128. A. S. Morel, N. Joris, R. Meuli, S. Jacquemont, D. Ballhausen, L. Bonafe, S. Fattet, J. F. Tolsa, 2009 Early neurological impairment and severe anemia in a newborn with Pearson syndrome. Eur J Pediatr 168. 3 311 5 .

  129. E. Morselli, L. Galluzzi, O. Kepp, J. M. Vicencio, A. Criollo, M. C. Maiuri, G. Kroemer, 2009 Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta 1793. 9 1524 32 .

  130. S. Mudaliar, R. R. Henry, 2001 New oral therapies for type 2 diabetes mellitus: The glitazones or insulin sensitizers. Annu Rev Med 52. 239 57 .

  131. H. Mulder, C. Ling, 2009 Mitochondrial dysfunction in pancreatic beta-cells in Type 2 diabetes. Mol Cell Endocrinol 297. 1-2: 34-40.

  132. S. Munusamy, Millan. Mac-Crow, L. A. , 2009 Mitochondrial superoxide plays a crucial role in the development of mitochondrial dysfunction during high glucose exposure in rat renal proximal tubular cells. Free Radic Biol Med 46. 8 1149 57 .

  133. S. Muraoka, T. Miura, 2003 [Free radicals mediate cardiac toxicity induced by adriamycin]. Yakugaku Zasshi 123. 10 855 66 .

  134. S. Nadanaciva, A. Bernal, R. Aggeler, R. Capaldi, Y. Will, 2007 Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays. Toxicol In Vitro 21. 5 902 11 .

  135. S. Nadanaciva, K. Dillman, D. F. Gebhard, A. Shrikhande, Y. Will, 2010 High-content screening for compounds that affect mtDNA-encoded protein levels in eukaryotic cells. J Biomol Screen 15. 8 937 48 .

  136. S. Nadanaciva, J. A. Dykens, A. Bernal, R. A. Capaldi, Y. Will, 2007 Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol Appl Pharmacol 223. 3 277 87 .

  137. S. Nadanaciva, Y. Will, 2009 The role of mitochondrial dysfunction and drug safety. IDrugs 12. 11 706 10 .

  138. K. Naess, C. Freyer, H. Bruhn, R. Wibom, G. Malm, I. Nennesmo, Dobeln. U. von, N. G. Larsson, 2009 MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome. Biochim Biophys Acta 1787. 5 484 90 .

  139. R. A. Nash, 2005 Metals in medicine. Altern Ther Health Med 11. 4 18 25 .

  140. T. Nishikawa, E. Araki, 2007 Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9. 3 343 53 .

  141. H. Nohl, D. de Silva, K. H. Summer, 1989 2,3,7,8, tetrachlorodibenzo-p-dioxin induces oxygen activation associated with cell respiration. Free Radic Biol Med 6. 4 369 74 .

  142. P. J. Oliveira, 2005 Cardiac mitochondrial alterations observed in hyperglycaemic rats--what can we learn from cell biology? Curr Diabetes Rev 1. 1 11 21 .

  143. P. J. Oliveira, J. A. Bjork, M. S. Santos, R. L. Leino, M. K. Froberg, A. J. Moreno, K. B. Wallace, 2004 Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 200. 2 159 68 .

  144. P. J. Oliveira, T. C. Esteves, R. Seica, A. J. Moreno, M. S. Santos, 2004 Calcium-dependent mitochondrial permeability transition is augmented in the kidney of Goto-Kakizaki diabetic rat. Diabetes Metab Res Rev 20. 2 131 6 .

  145. P. J. Oliveira, A. P. Rolo, R. Seica, C. M. Palmeira, M. S. Santos, A. J. Moreno, 2001 Decreased susceptibility of heart mitochondria from diabetic GK rats to mitochondrial permeability transition induced by calcium phosphate. Biosci Rep 21. 1 45 53 .

  146. P. J. Oliveira, M. S. Santos, K. B. Wallace, 2006 Doxorubicin-induced thiol-dependent alteration of cardiac mitochondrial permeability transition and respiration. Biochemistry (Mosc) 71. 2 194 9 .

  147. P. J. Oliveira, R. Seica, P. M. Coxito, A. P. Rolo, C. M. Palmeira, M. S. Santos, A. J. Moreno, 2003 Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS Lett 554. 3 511 4 .

  148. P. J. Oliveira, K. B. Wallace, 2006 Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats--relevance for mitochondrial dysfunction. Toxicology 220. 2-3: 160-8.

  149. H. M. Olson, C. C. Capen, 1978 Chemoresponsiveness of Moloney sarcoma virus-induced osteosarcoma to adriamycin in the rat. Cancer Res 38. 6 1561 7 .

  150. C. M. Palmeira, D. L. Santos, R. Seica, A. J. Moreno, M. S. Santos, 2001 Enhanced mitochondrial testicular antioxidant capacity in Goto-Kakizaki diabetic rats: role of coenzyme Q. Am J Physiol Cell Physiol 281. 3: C1023 8 .

  151. Andreu. G. L. Pardo, N. M. Inada, A. E. Vercesi, C. Curti, 2009 Uncoupling and oxidative stress in liver mitochondria isolated from rats with acute iron overload. Arch Toxicol 83. 1 47 53 .

  152. W. Parzefall, 2002 Risk assessment of dioxin contamination in human food. Food Chem Toxicol 40. 8 1185 9 .

  153. C. V. Pereira, A. C. Moreira, S. P. Pereira, N. G. Machado, F. S. Carvalho, V. A. Sardao, P. J. Oliveira, 2009 Investigating drug-induced mitochondrial toxicity: a biosensor to increase drug safety? Curr Drug Saf 4. 1 34 54 .

  154. G. C. Pereira, P. J. Oliveira, 2010 Pharmacological strategies to counteract doxorubicin-induced cardiotoxicity : the role of mitochondria. Journal of Theoretical and Experimental Pharmacology 1. 39 53 .

  155. S. P. Pereira, G. C. Pereira, A. J. Moreno, P. J. Oliveira, 2009 Can drug safety be predicted and animal experiments reduced by using isolated mitochondrial fractions? Altern Lab Anim 37. 4 355 65 .

  156. G. Perkins, E. Bossy-Wetzel, M. H. Ellisman, 2009 New insights into mitochondrial structure during cell death. Exp Neurol 218. 2 183 92 .

  157. K. F. Petersen, M. Krssak, S. Inzucchi, G. W. Cline, S. Dufour, G. I. Shulman, 2000 Mechanism of troglitazone action in type 2 diabetes. Diabetes 49. 5 827 31 .

  158. J. J. Poderoso, 2009 The formation of peroxynitrite in the applied physiology of mitochondrial nitric oxide. Arch Biochem Biophys 484. 2 214 20 .

  159. M. Praet, J. M. Ruysschaert, 1993 In-vivo and in-vitro mitochondrial membrane damages induced in mice by adriamycin and derivatives. Biochim Biophys Acta 1149. 1 79 85 .

  160. A. Quintana, S. E. Kruse, R. P. Kapur, E. Sanz, R. D. Palmiter, I. Complex, due. deficiency, loss. to, of, 4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proc Natl Acad Sci U S A 107. 24 10996 1001 .

  161. E. Quintana, J. A. Mayr, Silva. M. T. Garcia, A. Font, M. A. Tortoledo, S. Moliner, L. Ozaez, M. Lluch, A. Cabello, J. R. Ricoy, J. Koch, A. Ribes, W. Sperl, P. Briones, 2009 PDH E(1)beta deficiency with novel mutations in two patients with Leigh syndrome. J Inherit Metab Dis.

  162. L. I. Rachek, L. V. Yuzefovych, S. P. Ledoux, N. L. Julie, G. L. Wilson, 2009 Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes. Toxicol Appl Pharmacol 240. 3 348 54 .

  163. A. Rami, 2009 Review: autophagy in neurodegeneration: firefighter and/or incendiarist? Neuropathol Appl Neurobiol 35. 5 449 61 .

  164. P. V. Reddy, K. V. Rao, M. D. Norenberg, 2008 The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes. Lab Invest 88. 8 816 30 .

  165. E. Reich, D. J. Luck, 1966 Replication and inheritance of mitochondrial DNA. Proc Natl Acad Sci U S A 55. 6 1600 8 .

  166. X. Y. Ren, Y. N. Li, J. S. Qi, T. Niu, 2008 Peroxynitrite-induced protein nitration contributes to liver mitochondrial damage in diabetic rats. J Diabetes Complications 22. 5 357 64 .

  167. D. S. Robinson, D. L. Roberts, J. M. Smith, J. C. Stringfellow, S. B. Kaplita, J. A. Seminara, R. N. Marcus, 1996 The safety profile of nefazodone. J Clin Psychiatry 57 Suppl 2. 31 8 .

  168. R. Rossignol, B. Faustin, C. Rocher, M. Malgat, J. P. Mazat, T. Letellier, 2003 Mitochondrial threshold effects. Biochem J 370. Pt 3 751 62 .

  169. R. Rossignol, R. Gilkerson, R. Aggeler, K. Yamagata, S. J. Remington, R. A. Capaldi, 2004 Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64. 3 985 93 .

  170. X. Saelens, N. Festjens, Walle. L. Vande, M. van Gurp, G. van Loo, P. Vandenabeele, 2004 Toxic proteins released from mitochondria in cell death. Oncogene 23. 16 2861 74 .

  171. D. L. Santos, C. M. Palmeira, R. Seica, J. Dias, J. Mesquita, A. J. Moreno, M. S. Santos, 2003 Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat. Mol Cell Biochem 246. 1-2: 163-70.

  172. V. A. Sardao, P. J. Oliveira, J. Holy, C. R. Oliveira, K. B. Wallace, 2009 Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets. Cell Biol Toxicol 25. 3 227 43 .

  173. D. B. Sawyer, X. Peng, B. Chen, L. Pentassuglia, C. C. Lim, 2010 Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis 53. 2 105 13 .

  174. R. Scatena, P. Bottoni, G. Botta, G. E. Martorana, B. Giardina, 2007 The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic. Am J Physiol Cell Physiol 293. 1: C12 21 .

  175. R. Scatena, P. Bottoni, G. E. Martorana, F. Ferrari, P. De Sole, C. Rossi, B. Giardina, 2004 Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications. Biochem Biophys Res Commun 319. 3 967 73 .

  176. R. Scatena, G. E. Martorana, P. Bottoni, B. Giardina, 2004 Mitochondrial dysfunction by synthetic ligands of peroxisome proliferator activated receptors (PPARs). IUBMB Life 56. 8 477 82 .

  177. C. F. Schaars, A. F. Stalenhoef, 2008 Effects of ubiquinone (coenzyme Q10) on myopathy in statin users. Curr Opin Lipidol 19. 6 553 7 .

  178. Z. T. Schug, E. Gottlieb, 2009 Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta 1788. 10 2022 31 .

  179. J. L. Seachrist, C. M. Loi, M. G. Evans, K. A. Criswell, C. E. Rothwell, 2005 Roles of exercise and pharmacokinetics in cerivastatin-induced skeletal muscle toxicity. Toxicol Sci 88. 2 551 61 .

  180. A. P. Senft, T. P. Dalton, D. W. Nebert, M. B. Genter, R. J. Hutchinson, H. G. Shertzer, 2002 Dioxin increases reactive oxygen production in mouse liver mitochondria. Toxicol Appl Pharmacol 178. 1 15 21 .

  181. A. P. Senft, T. P. Dalton, D. W. Nebert, M. B. Genter, A. Puga, R. J. Hutchinson, J. K. Kerzee, S. Uno, H. G. Shertzer, 2002 Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radic Biol Med 33. 9 1268 78 .

  182. G. S. Shadel, 2005 Mitochondrial DNA, aconitase ‘wraps’ it up. Trends Biochem Sci 30. 6 294 6 .

  183. Dein. O. Sharaf El, C. Gallerne, A. Deniaud, C. Brenner, C. Lemaire, 2009 Role of the permeability transition pore complex in lethal inter-organelle crosstalk. Front Biosci 14. 3465 82 .

  184. D. Shen, T. P. Dalton, D. W. Nebert, H. G. Shertzer, 2005 Glutathione redox state regulates mitochondrial reactive oxygen production. J Biol Chem 280. 27 25305 12 .

  185. B. J. Shenker, T. L. Guo, I. M. Shapiro, 1998 Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction. Environ Res 77. 2 149 59 .

  186. C. Sheridan, S. J. Martin, 2010 Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion 10. 6 640 8 .

  187. H. G. Shertzer, M. B. Genter, D. Shen, D. W. Nebert, Y. Chen, T. P. Dalton, 2006 TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F(0)F(1)-ATP synthase and ubiquinone. Toxicol Appl Pharmacol 217. 3 363 74 .

  188. L. M. Shi, H. Jiang, J. Wang, Z. G. , J. X. Xie, 2008 Mitochondria dysfunction was involved in copper-induced toxicity in MES23.5 cells. Neurosci Bull 24. 2 79 83 .

  189. P. K. Singal, N. Iliskovic, T. Li, D. Kumar, 1997 Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 11. 12 931 6 .

  190. G. Solaini, A. Baracca, G. Lenaz, G. Sgarbi, 2010 Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta 1797. 6-7: 1171-7.

  191. Y. O. Son, J. C. Lee, J. A. Hitron, J. Pan, Z. Zhang, X. Shi, 2011 Cadmium induces intracellular Ca2+- and H2O2-dependent apoptosis through JNK- and 53 pathways in skin epidermal cell line. Toxicol Sci 113. 1: 127-37.

  192. V. Soubannier, H. M. Mc Bride, 2009 Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793. 1 154 70 .

  193. M. E. Souza, A. C. Polizello, S. A. Uyemura, O. Castro-Silva, C. Curti, 1994 Effect of fluoxetine on rat liver mitochondria. Biochem Pharmacol 48. 3 535 41 .

  194. G. Steiner, 2007 Atherosclerosis in type 2 diabetes: a role for fibrate therapy? Diab Vasc Dis Res 4. 4 368 74 .

  195. S. J. Stohs, N. Z. Alsharif, M. A. Shara, Z. A. al-Bayati, Z. Z. Wahba, 1991 Evidence for the induction of an oxidative stress in rat hepatic mitochondria by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Adv Exp Med Biol 283. 827 31 .

  196. S. J. Stohs, D. Bagchi, 1995 Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18. 2 321 36 .

  197. M. H. Sweeney, P. Mocarelli, 2000 Human health effects after exposure to 2,3,7,8-TCDD. Food Addit Contam 17. 4 303 16 .

  198. E. Szabados, G. M. Fischer, K. Toth, B. Csete, B. Nemeti, K. Trombitas, T. Habon, D. Endrei, B. Sumegi, 1999 Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. Free Radic Biol Med 26. 3-4: 309-17.

  199. S. W. Tait, D. R. Green, 2010 Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11. 9 621 32 .

  200. M. A. Tirmenstein, C. X. Hu, T. L. Gales, B. E. Maleeff, P. K. Narayanan, E. Kurali, T. K. Hart, H. C. Thomas, L. W. Schwartz, 2002 Effects of troglitazone on HepG2 viability and mitochondrial function. Toxicol Sci 69. 1 131 8 .

  201. M. Tokarska-Schlattner, M. Zaugg, C. Zuppinger, T. Wallimann, U. Schlattner, 2006 New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. J Mol Cell Cardiol 41. 3 389 405 .

  202. I. V. Turko, L. Li, K. S. Aulak, D. J. Stuehr, J. Y. Chang, F. Murad, 2003 Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes. J Biol Chem 278. 36 33972 7 .

  203. G. Twig, S. A. Graf, J. D. Wikstrom, H. Mohamed, S. E. Haigh, A. Elorza, M. Deutsch, N. Zurgil, N. Reynolds, O. S. Shirihai, 2006 Tagging and tracking individual networks within a complex mitochondrial web with photoactivatable GFP. Am J Physiol Cell Physiol 291. 1: C176 84 .

  204. C. Ulivieri, 2010 Cell death: insights into the ultrastructure of mitochondria. Tissue Cell 42. 6 339 47 .

  205. D. Valenti, A. Atlante, M. Barile, S. Passarella, 2002 Inhibition of phosphate transport in rat heart mitochondria by 3’-azido-3’-deoxythymidine due to stimulation of superoxide anion mitochondrial production. Biochem Pharmacol 64. 2 201 6 .

  206. D. Valenti, M. Barile, S. Passarella, 2000 AZT inhibition of the ADP/ATP antiport in isolated rat heart mitochondria. Int J Mol Med 6. 1 93 6 .

  207. B. Van Houten, V. Woshner, J. H. Santos, 2006 Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst) 5. 2 145 52 .

  208. J. A. Velho, H. Okanobo, G. R. Degasperi, M. Y. Matsumoto, L. C. Alberici, R. G. Cosso, H. C. Oliveira, A. E. Vercesi, 2006 Statins induce calcium-dependent mitochondrial permeability transition. Toxicology 219. 1-3: 124-32.

  209. J. Vockley, D. A. Whiteman, 2002 Defects of mitochondrial beta-oxidation: a growing group of disorders. Neuromuscul Disord 12. 3 235 46 .

  210. U. A. Walker, J. Bauerle, M. Laguno, J. Murillas, S. Mauss, G. Schmutz, B. Setzer, R. Miquel, J. M. Gatell, J. Mallolas, 2004 Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology 39. 2 311 7 .

  211. D. C. Wallace, 2000 Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J 139. 2 Pt 3: S70 85 .

  212. D. C. Wallace, W. Fan, 2010 Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10. 1 12 31 .

  213. K. B. Wallace, 2003 Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 93. 3 105 15 .

  214. K. B. Wallace, 2008 Mitochondrial off targets of drug therapy. Trends Pharmacol Sci 29. 7 361 6 .

  215. J. G. Wallenborn, M. J. Schladweiler, J. H. Richards, U. P. Kodavanti, 2009 Differential pulmonary and cardiac effects of pulmonary exposure to a panel of particulate matter-associated metals. Toxicol Appl Pharmacol 241. 1 71 80 .

  216. C. Wang, R. J. Youle, 2009 The role of mitochondria in apoptosis*. Annu Rev Genet 43. 95 118 .

  217. O. Warburg, 1930 The Metabolism of Tumors. London, Arnold Constable.

  218. O. Warburg, 1956 On respiratory impairment in cancer cells. Science 124. 3215 269 70 .

  219. O. Warburg, 1956 On the origin of cancer cells. Science 123. 3191 309 14 .

  220. C. E. Wenner, S. Weinhouse, 1953 Metabolism of neoplastic tissue. III. Diphosphopyridine nucleotide requirements for oxidations by mitochondria of neoplastic and non-neoplastic tissues. Cancer Res 13. 1 21 6 .

  221. F. R. Westwood, A. Bigley, K. Randall, A. M. Marsden, R. C. Scott, 2005 Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity. Toxicol Pathol 33. 2 246 57 .

  222. Y. Will, J. Hynes, V. I. Ogurtsov, D. B. Papkovsky, 2006 Analysis of mitochondrial function using phosphorescent oxygen-sensitive probes. Nat Protoc 1. 6 2563 72 .

  223. W. W. Wong, H. Puthalakath, 2008 Bcl-2 family proteins: the sentinels of the mitochondrial apoptosis pathway. IUBMB Life 60. 6 390 7 .

  224. W. Z. Wu, W. Li, Y. Xu, J. W. Wang, 2001 Long-term toxic impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the reproduction, sexual differentiation, and development of different life stages of Gobiocypris rarus and Daphnia magna. Ecotoxicol Environ Saf 48. 3 293 300 .

  225. S. J. Yeung, J. Pan, M. H. Lee, 2008 Roles of 53 MYC and HIF-1 in regulating glycolysis- the seventh hallmark of cancer. Cell Mol Life Sci 65. 24: 3981-99.

  226. S. B. Yoon, K. Kajiyama, Y. Hino, M. Sugiyama, R. Ogura, 1983 Effect of adriamycin on lipid peroxide, glutathione peroxidase and respiratory responses of mitochondria from the heart, liver and kidney. Kurume Med J 30. 1 1 4 .

  227. R. J. Youle, D. P. Narendra, 2011 Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12. 1 9 14 .

  228. G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J. Ventre, T. Doebber, N. Fujii, N. Musi, M. F. Hirshman, L. J. Goodyear, D. E. Moller, 2001 Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108. 8 1167 74 .

  229. S. Zhou, A. Starkov, M. K. Froberg, R. L. Leino, K. B. Wallace, 2001 Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61. 2 771 7 .

  230. M. Zick, R. Rabl, A. S. Reichert, 2009 Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta 1793. 1 5 19 .

  231. D. B. Zorov, M. Juhaszova, Y. Yaniv, H. B. Nuss, S. Wang, S. J. Sollott, 2009 Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res 83. 2 213 25 .