The Role of Mitochondrial DNA Alterations in Cancer

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DESCRIPTION (provided by applicant): The importance of mitochondria in energy metabolism, generation of reactive oxygen species (ROS), aging, and the initiation of apoptosis, have suggested that mitochondria are indispensable integrators in the pathways of tumorigenesis. The close proximity of mitochondria to the ROS producing sites, the limited DNA repair capabilities, and the lack of protective histone proteins render high susceptibility of mtDNA to mutations. Somatic mitochondrial DNA (mtDNA) mutation has been reported in solid tumors including breast, lung, bladder, ovarian, and colon; and has been regarded as a general phenomenon of cancer. However, the functional significance of these mutations has never been investigated. Marked reduction in the cellular content of mitochondria associated with elevated glycolytic activity is an abnormal bio-energetic phenotype of cancer. Both down-regulated and elevated mitochondrial gene expression have been observed in neoplastic cells. Defective mitochondria in tumor cells are constantly under oxidative stress that would generate higher levels of ROS and cause more mutations in genes involved in the regulation of cell growth and ATP production. To this day, the role that mitochondria play in the development of cancer and in maintaining uncontrolled cell growth remains unknown. Recent reports on transmitochondrial cybrid studies demonstrated that mitochondria bearing mutations causing Leber's hereditary optic neuropathy (LHON) are more sensitive to apoptosis. Our hypothesis is that if there are mutant mitochondria that are more sensitive to cell death in neuro-degeneration disease, there will be mitochondrial DNA mutants in cancer cells that are more resistant to apoptosis. To support the hypothesis, we plan to (1) identify somatic mtDNA mutations by the analysis of the entire mitochondrial genome in normal/tumor pairs of breast carcinomas and cell lines, (2) evaluate the mtDNA content that reflects the biogenesis of mitochondria in tumor, (3) determine the potential functional significance of the mtDNA mutations, and (4) assess the effect of mutant mitochondria on cellular response to apoptotic treatment by using the transmitochondrial cybrid cell system. Results from this research project will help us understand the functional role of mitochondrial DNA alterations in cancer and identify potential novel targets for more effective therapeutic development.