Mitochondria as a Target of Environmental Toxicants

Toxicological Sciences, Jul 2013

Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria.

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Mitochondria as a Target of Environmental Toxicants

Joel N.Meyer 2 Maxwell C.K.Leung J 2 ohn P.Rooney 2 AtamanSendoel 0 Michael O.Hengartner 0 Glen E.Kisby 1 Amanda S.Bess 2 0 Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland 1 Department of Basic Medical Sciences, Western University of Health Sciences , Lebanon, Oregon 2 Nicholas School of the Environment, Duke University , Durham, North Carolina Received January 23, 2013; accepted April 23, 2013 ow cular intron-free genome consisting of 14,00017,000 base pamirstDNA and nDNA Mutations Can Cause Mitochondrial r21 Lessons from Mitochondrial Diseases Another example is the nucleoside reverse transcriptase Fig.2. Factors that affect mitochondrial vulnerability to environmental toxicants, as discussed in the text. mtDNA Exhibits Unique Vulnerabilities But May Be genome were differentially packaged, so different regions mr2ay Developmental Stage Modulates Sensitivity 2002; Hebertetal., 2010; Jansen and de Boer, 1998K; nudsen oD Beckman, K. B., and Ames, B. N. (1998). Mitochondrial aging: Open ques tions. Ann. N.Y. Acad. Sci. 854, 118127. Fu NDi Ng Begriche, K., Igoudjil, A., Pessayre, D., and Fromenty, B. (2006). Mitochondrial dysfunction in NASH: Causes, consequences and possible means to prevent it. Mitochondrion 6, 128. National Institute of Environmental Health Sciences (1R01 Begriche, K., Massart, J., Robin, M. A., Borgne-Sanchez, A., and Fromenty, ES017540-01A2, P42 ES010356-10A2). B. (2011). Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver. J. Hepatol. 54, 773794. rEFE r ENc Es Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V., and Zakharova, I. O. (2012). Mitochondrial electron transport chain in heavy metal-induced neuAmes, B. N., Shigenaga, M. K., and Hagen, T. M. (1995). Mitochondrial decay rotoxicity: Effects of cadmium, mercury, and copper. ScientificWorldJournal. in aging. Biochim. Biophys. Acta 1271, 165170. 2012, 136063. Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H., Coulson, A. R.B,enhammou, V., Tardieu, M., Warszawski, J., Rustin, P., and Blanche, S. Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., etal. (1981). (2007). Clinical mitochondrial dysfunction in uninfected children born to parkinsonism mediates the incorporation and translesion synthesis oppJoasnitseen, R. P. (2000). Germline passage of mitochondria: Quantitative consid7,8-dihydro-8-oxo-2-deoxyguanosine. Hum. Mol. Genet. 16, 27292739. erations and possible embryological sequelae. Hum. Re1p5ro(Sd.uppl.2), Graziewicz, M. A., Sayer, J. M., Jerina, D. M., and Copeland, W. C. (2004). 112128. Nucleotide incorporation by human DNA polymerase gamma opposJitaensen, R. P., and Burton, G. J. (2004). Mitochondrial dysfunction in reproducbenzo[a]pyrene and benzo[c]phenanthrene diol epoxide adducts of deoxyt-ion. Mitochondrion 4, 577600. guanosine and deoxyadenosine. Nucleic Acids Res. 32, 397405. Koczor, C. A., Shokolenko, I. N., Boyd, A. K., Balk, S. P., Wilson, G. L., and longevity: Loss of mclk1 increases cellular fitness and lifespan in mice. Ledoux, S. P. (2009). Mitochondrial DNA damage initiates a cell cycle arreGstenes Dev. 19, 24242434. by a Chk2-associated mechanism in mammalian cells. J. Biol. C2h8e4m,. 3619136201. Leung, M. C., Rooney, J. P., Ryde, I. T., Bernal, A. J., Bess, A. S., Crocker, T. L., Ji, A. Q., and Meyer, J. N. (2013). Effects of early life exposure toMeyer, J. N. (2010). QPCR: Atool for analysis of mitochondrial and nuclear ultraviolet C radiation on mitochondrial DNA content, transcription, DANTPA damage in ecotoxicology. Ecotoxicology 19, 804811. production, and oxygen consumption in developing Caenorhabditis elegManeys.er, J. N., and Bess, A. S. (2012). Involvement of autophagy and mitochonBMC Pharmacol. Toxicol. 14, 9. drial dynamics in determining the fate and effects of irreparable mitochonLi, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J. A., and drial DNA damage. Autophagy 8, 18221823. Robinson, J. P. (2003a). DPI induces mitochondrial superoxide-mediateMdeyer, J. N., Boyd, W. A., Azzam, G. A., Haugen, A. C., Freedman, J. H., and apoptosis. Free Radic. Biol. Med. 34, 465477. Van Houten, B. (2007). Decline of nucleotide excision repair capacity in Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J. A., and aging Caenorhabditis elegans. Genome Biol. 8, R70. Robinson, J. P. (2003b). Mitochondrial complex Iinhibitor rotenone induMceisjaljica, D., Prescott, M., and Devenish, R. J. (2007). Different fates of mitoapoptosis through enhancing mitochondrial reactive oxygen species produch-ondria: Alternative ways for degradation? Autophagy 3, 49. tion. J. Biol. Chem. 278, 85168525. (...truncated)


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Joel N. Meyer, Maxwell C. K. Leung, John P. Rooney, Ataman Sendoel, Michael O. Hengartner, Glen E. Kisby, Amanda S. Bess. Mitochondria as a Target of Environmental Toxicants, Toxicological Sciences, 2013, pp. 1-17, 134/1, DOI: 10.1093/toxsci/kft102