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Can environmental exposures that damage mitochondria contribute to cancer? Joel Meyer Duke University Durham, North Carolina USA Chronic diseases such as cancer will be increasingly important in the future -- Cancer is the leading cause of death in many high-income countries (In US in 2009: ~560,000 deaths, $240 billion). -- Incidence increasing: over 22 million new cancer cases projected annually by 2030, up from 12.7 million in 2008. * -- Treatments very costly and not always effective. -- Prevention is important! What causes cancer? *Bray et al. Lancet Oncology S1470-2045(12)70211-5, 2012 Can environmental exposures that damage mitochondria contribute to cancer? I. Environment and cancer II. Mitochondria and cancer III. Environment and mitochondria IV. Can environmental exposures that damage mitochondria contribute to cancer? Nature vs nurture (genes vs environment) in cancer 15-30% of risk of most cancers is genetic. What accounts for the rest? -- environment “The Panel was particularly concerned to find that the true burden of environmentally induced cancer has been grossly underestimated.” President’s Cancer Panel 2009 http://www.ncbi.nlm.nih.gov/pubmed/24659601 http://www.ncbi.nlm.nih.gov/pubmed/11979442 http://www.ncbi.nlm.nih.gov/pubmed/10891514 Which environmental factors matter? “Other than genetic” …is a very broad definition of… “environment” Rappaport, 2012 The same exposure affects different people differently Environmentally caused diseases are influenced by genetic susceptibility. – More than 90% of lung cancer is caused by cigarette smoking; only 10%-15% of smokers will develop lung cancer. Why? - Genetic variation - Disease - Dietary and other lifestyle differences - Other chemical exposures - Other How can environmental exposures cause cancer? Exposure leads to mutation or signaling, which alter the function of genes in critical pathways. Luch, 2005 Outline I. Environment and cancer II. Mitochondria and cancer III. Environment and mitochondria IV. Can environmental exposures that damage mitochondria contribute to cancer? Why do we have mitochondria? ATP: energy (“powerhouse of the cell”) Apoptosis, thermogenesis, steroid synthesis, heme synthesis, epigenetic cofactors, and more! The mitochondrial genome Small, 1000s/cell (usually) Importance: diseases effects of drugs mtRNAs 5-30% of cellular mRNA Sensitivity to many genotoxicants, limited repair Mitochondria generate reactive oxygen species and attract many pollutants (Meyer et al., 2013) Is altered mitochondrial function one of the critical cancer pathways? -- Cancer cells often exhibit aerobic glycolysis (Warburg effect). -- Mutations in genes coding mitochondrial proteins cause some cancers. -- Cancerous cells often have a high level of mutations in the mitochondrial genome. -- Mitochondrial regulation of calcium levels, reactive oxygen species, apoptosis, epigenetics, and more… Outline I. Environment and cancer II. Mitochondria and cancer III. Environment and mitochondria IV. Can environmental exposures that damage mitochondria contribute to cancer? Mitochondrial DNA is particularly sensitive to important pollutants Also: aflatoxin, hydrogen peroxide, benzo[a]pyrene, many others (reviewed in Meyer et al., 2013) González-Hunt et al., 2014 Some mitochondrial DNA damage is irreparable UV radiation Meyer et al., 2007 Environmental exposures often cause irreparable mtDNA damage Polycyclic aromatic hydrocarbons mycotoxins UV radiation Outline I. Environment and cancer II. Mitochondria and cancer III. Environment and mitochondria IV. Can environmental exposures that damage mitochondria contribute to cancer? Model organism: Caenorhaditis elegans -- transparent 1 mm nematode -- 3-4 day generation time -- hundreds of progeny -- excellent genetic, genomic tools -- grown on solid or in liquid media; relatively cheap and easy to maintain -- good model for cancerrelated processes. What happens to mitochondrial function later in life after early-life mtDNA damage? Days Persistent mtDNA damage in larvae results in life-long reduction in ATP How is mitochondrial metabolism reset? -- insufficient mtDNA templates? --insufficient mtRNAs? Stay tuned! Arsenic is a mitochondrial toxicant Arsenite (AsIII) & metabolites inhibit many key mitochondrial enzymes and lead to mitochondrial dysfunction Mitochondrial fusion-deficient mutants are hypersensitive to arsenite-induced reduction in spare respiratory capacity Conclusions Environmental contributions to cancer are poorly understood Frontier: the role of mitochondrial dysfunction in cancer (better understanding treatment) Frontier: the role of pollutants in altering mitochondrial function in cancer (better understanding prevention) Frontier: understanding which people will be most senstive (better understanding prevention and treatment)