Current Concepts in Drug‐Induced Mitochondrial Toxicity

Sashi Nadanaciva1, Yvonne Will1

1 Pfizer Inc., Groton, Connecticut
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 2.15
DOI:  10.1002/0471140856.tx0215s40
Online Posting Date:  May, 2009
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Mitochondria generate most of the cell's ATP and play key roles in fatty acid oxidation, steroid synthesis, heme synthesis, thermogenesis, calcium homeostasis, and apoptosis. With the development of new methods to study mitochondrial function, it is becoming clear that drug‐induced mitochondrial dysfunction is one of the causes of drug toxicity. Mitochondria can be impaired by drugs in a variety of ways. These include inhibition of oxidative phosphorylation, uncoupling of electron transport from ATP synthesis, irreversible opening of the mitochondrial permeability transition pore, inhibition of transporters within the mitochondrial inner membrane, increased oxidative stress, inhibition of the citric acid cycle, inhibition of fatty acid oxidation, and impairment of either mtDNA replication or mtDNA‐encoded protein synthesis. This unit provides an overview on the physiological roles of mitochondria and the mechanisms by which they can be adversely affected by drugs. Curr. Protoc. Toxicol. 40:2.15.1‐2.15.9. © 2009 by John Wiley & Sons, Inc.

Keywords: toxicity; mitochondria; energy production; ROS; apoptosis; mtDNA; mt ribosomes; drug toxicity

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Energy Production in Mitochondria
  • Mitochondria and Reactive Oxygen Species
  • Mitochondria and Apoptosis
  • Mitochondrial DNA and Mitochondrial Ribosomes
  • Drug‐Induced Mitochondrial Toxicity
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   Adam‐Vizi, V. and Chinopoulos, C. 2006. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci. 27:639‐645.
   Benbrik, E., Chariot, P., Bonavaud, S., Ammi‐Said, M., Frisdal, E., Rey, C., Gherardi, R., and Barlovatz‐Meimon, G. 1997. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J. Neurol. Sci. 149:19‐25.
   Berman, S.B., Pineda, F.J., and Hardwick, J.M. 2008. Mitochondrial fission and fusion dynamics: The long and short of it. Cell Death Differ. 15:1147‐1152.
   Berson, A., Cazanave, S., Descatoire, V., Tinel, M., Grodet, A., Wolf, C., Feldmann, G., and Pessayre, D. 2006. The anti‐inflammatory drug, nimesulide (4‐nitro‐2‐phenoxymethane‐sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: Protection by albumin. Pharmacol. Exp. Ther. 318:444‐454.
   Berthiaume, J.M. and Wallace, K.B. 2007. Adriamycin‐induced oxidative mitochondrial cardiotoxicity. Cell Biol. Toxicol. 23:15‐25.
   Boelsterli, U.A. 2007. Disruption of mitochondrial function and mitochondria‐mediated toxicity In Mechanistic Toxicology (U.A. Boelsterli, ed.) pp. 357‐383. CRC Press, Taylor & Francis Group, Boca Raton, Fla.
   Böttger, E.C. 2007. Antimicrobial agents targeting the ribosome: The issue of selectivity and toxicity—Lessons to be learned. Cell. Molec. Life Sci. 64:791‐795.
   Brunmair, B., Lest, A., Staniek, K., Gras, F., Scharf, N., Roden, M., Nohl, H., Waldhäusl, W., and Fürnsinn, C. 2004. Fenofibrate impairs rat mitochondrial function by inhibition of respiratory control complex I. J. Pharmacol. Exp. Ther. 311:109‐114.
   Chan, K., Truong, D., Shangari, N., and O'Brien, P.J. 2005. Drug‐induced mitochondrial toxicity. Expert Opin. Drug Metab. Toxicol. 1:655‐669.
   Chipuk, J.E. and Green, D.R. 2008. How do BCL‐2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 18:157‐164.
   Cunarro, J. and Weiner, M.W. 1975. Mechanism of action of agents which uncouple oxidative phosphorylation: Direct correlation between proton carrying and respiratory‐releasing properties using rat liver mitochondria. Biochim. Biophys. Acta 387:234‐240.
   de Baar, M.P. and de Ronde, A. 2008. Mitochondrial toxicity of antiviral drugs: A challenge to accurate diagnosis. In Drug‐Induced Mitochondrial Dysfunction (J.A. Dykens and Y. Will, eds.) pp. 473‐492. John Wiley & Sons, Inc., Hoboken, N.J.
   Dykens, J.A., and Will, Y. 2007. The significance of mitochondrial toxicity testing in drug development. Drug Discov. Today 12:777‐785.
   Dykens, J.A., Marroquin, L.D., and Will, Y. 2007. Strategies to reduce late‐stage drug attrition due to mitochondrial toxicity. Expert Rev. Mol. Diagn. 7:161‐175.
   Dykens, J.A., Jamieson, J.D., Marroquin, L.D., Nadanaciva, S., Xu, J.J., Dunn, M.C., Smith, A.R., and Will, Y. 2008a. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol. Sci. 103:335‐345.
   Dykens, J.A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P.A., and Will, Y. 2008b. Biguanide‐induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically‐poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 233:203‐210.
   Green, D.R. 2005. Apoptotic pathways: Ten minutes to dead. Cell. 121:671‐674.
   Haasio, K., Koponen, A., Penttilä, K.E., and Nissinen, E. 2002. Effects of entacapone and tolcapone on mitochondrial membrane potential. Eur. J. Pharmacol. 453:21‐26.
   Han, D., Matsumaru, K., Rettori, D., and Kaplowitz, N. 2004. Usnic acid‐induced necrosis of cultured mouse hepatocytes: Inhibition of mitochondrial function and oxidative stress. Biochem. Pharmacol. 67:439‐451.
   Kaufmann, P., Torok, M., Zahno, A., Waldhauser, K.M., Brecht, K., and Krahenbuhl, S. 2006. Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol. Life Sci. 63:2415‐2425.
   Kinnally, K.W. and Antonsson, B. 2007. A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis 12:857‐868.
   Kroemer, G., Galluzzi, L., and Brenner, C. 2007. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87:99‐163.
   Krueger, M.J., Singer, T.P., Casida, J.E., and Ramsay, R.R. 1990. Evidence that the blockade of mitochondrial respiration by the neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP+) involves binding at the same site as the respiratory inhibitor, rotenone. Biochem. Biophys. Res. Commun. 169:123‐128.
   Labbe, G., Pessayre, D., and Fromenty, B. 2008. Drug‐induced liver injury through mitochondrial dysfunction: Mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22:335‐353.
   Lee, J., Sharma, S., Kim, J., Ferrante, R.J., and Ryu, H. 2008. Mitochondrial nuclear receptors and transcription factors: Who's minding the cell? J. Neurosci. Res. 86:961‐971.
   Liébecq, C. and Peters, R.A. 1989. The toxicity of fluoroacetate and the tricarboxylic acid cycle. Biochim. Biophys. Acta. 1000:254‐269.
   Masubuchi, Y., Nakayama, S., and Horie, T. 2002. Role of mitochondrial permeability transition in diclofenac‐induced hepatocyte injury in rats. Hepatology 35:544‐551.
   Masubuchi, Y., Kano, S., and Horie, T. 2006. Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones. Toxicology 222:233‐239.
   Maurer, I. and Möller, H.J. 1997. Inhibition of complex I by neuroleptics in normal human brain cortex parallels the extrapyramidal toxicity of neuroleptics. Mol. Cell Biochem. 174:255‐259.
   McKee, E.E. 2008. Assessing mitochondrial protein synthesis in drug toxicity screening. In Drug‐Induced Mitochondrial Dysfunction (J.A. Dykens and Y. Will, eds.) pp. 463‐472. John Wiley & Sons, Inc., Hoboken, N.J.
   McKee, E.E., Ferguson, M., Bentley, A.T., and Marks, T.A. 2006. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrobial Agents Chemo. 50:2042‐2049.
   Mehta, R., Chan, K., Lee, O., Tafazoli, S., and O'Brien, P.J. 2008. Drug‐associated mitochondrial toxicity. In Drug‐Induced Mitochondrial Dysfunction (J.A. Dykens and Y. Will, eds.) pp. 71‐126. John Wiley & Sons, Inc., Hoboken, N.J.
   Modjtahedi, N., Giordanetto, F., Madeo, F., and Kroemer, G. 2006. Apoptosis‐inducing factor: Vital and lethal. Trends Cell Biol. 16:264‐272.
   Nadanaciva, S., Dykens, J.A., Bernal, A., Capaldi, R.A., and Will, Y. 2007. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol. Appl. Pharmacol. 223:277‐287.
   Ong, M.M., Latchoumycandane, C., and Boelsterli, U.A. 2007. Troglitazone‐induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol. Sci. 97:205‐213.
   Ow, Y.L., Green, D.R., Hao, Z., and Mak, T.W. 2008. Cytochrome c: Functions beyond respiration. Nat. Rev. Mol. Cell Biol. 9:532‐542.
   Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E., Walford, G.A., Sugiana, C., Boneh, A., Chen, W.K., Hill, D.E., Vidal, M., Evans, J.G., Thorburn, D.R., Carr, S.A., and Mootha, V.K. 2008. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112‐123.
   Psarra, A.M. and Sekeris, C.E. 2008. Nuclear receptors and other nuclear transcription factors in mitochondria: Regulatory molecules in a new environment. Biochim. Biophys. Acta 1783:1‐11.
   Scatena, R., Bottoni, P., Botta, G., Martorana, G.E., and Giardina, B. 2007. The role of mitochondria in pharmacotoxicology: A reevaluation of an old, newly emerging topic. Am. J. Physiol. Cell Physiol. 293:C12‐C21.
   Scheffler, I.E. 2007. Mitochondrial electron transfer and oxidative phosphorylation. In Mitochondria (I.E. Scheffler, ed.) pp. 168‐297. John Wiley & Sons, Inc., Hoboken, N.J.
   Scheffler, I.E., 2008. Basic molecular biology of mitochondrial replication In Drug‐Induced Mitochondrial Dysfunction (J.A. Dykens and Y. Will, eds.) pp. 37‐70. John Wiley & Sons, Inc., Hoboken, N.J.
   Tay, V.K., Wang, A.S., Leow, K.Y., Ong, M.M., Wong, K.P., and Boelsterli, U.A. 2005. Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro. Free Radic. Biol. Med. 39:949‐959.
   Taylor, S.W., Fahy, E., Zhang, B., Glenn, G.M., Warnock, D.E., Wiley, S., Murphy, A.N., Gaucher, S.P., Capaldi, R.A., Gibson, B.W., and Ghosh, S.S. 2003. Characterization of the human heart mitochondrial proteome. Nat. Biotechnol. 21:281‐286.
   Tirmenstein, M.A., Hu, C.X., Gales, T.L., Maleeff, B.E., Narayanan, P.K., Kurali, E., Hart, T.K., Thomas, H.C., and Schwartz, L.W. 2002. Effects of troglitazone on HepG2 viability and mitochondrial function. Toxicol. Sci. 69:131‐138.
   Turrens, J.F. 2003. Mitochondrial formation of reactive oxygen species. J. Physiol. 552:335‐344.
   Wallace, K.B. 2008. Mitochondrial off targets of drug therapy. Trends Pharmacol. Sci. 29:361‐366.
   Wallace, K.B. and Starkov, A. 2000. Mitochondrial targets of drug toxicity. Ann. Rev. Pharmacol. Toxicol. 40:353‐388.
   Wang, D.S., Kusuhara, H., Kato, Y., Jonker, J.W., Schinkel, A.H., and Sugiyama, Y. 2003. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol. Pharmacol. 63:844‐848.
   Wojtczak, L. and Zablocki, K. 2008. Basic mitochondrial physiology in cell viability and death. In Drug‐Induced Mitochondrial Dysfunction (J.A. Dykens and Y. Will, eds.) pp. 3‐35. John Wiley & Sons, Inc., Hoboken, N.J.
   Zhou, S. and Wallace, K.B. 1999. The effect of peroxisome proliferators on mitochondrial bioenergetics. Toxicol. Sci. 48:82‐89.
PDF or HTML at Wiley Online Library