(PQ5) Role of Mitochondrial Division in Cancer Biology

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 DESCRIPTION (provided by applicant): The impact of mitochondrial biology on human cancers is broad because these organelles are critical regulators of metabolism, proliferation, and apoptosis. Indeed, mitochondrial aberrations are common in multiple cancer types --- not only do mitochondrial dysfunctions correlate with disease pathogenesis, but aberrant mitochondria also negatively impact upon chemotherapeutic success. Within a cell, mitochondrial homeostasis is maintained by a process referred to as "mitochondrial dynamics", which is essential for mitochondrial genome integrity, efficient ATP generation, managing ROS, and the rapid distribution of mitochondrial metabolites. Mitochondrial dynamics result from the cumulative nature of two opposing forces: mitochondrial division and mitochondrial fusion. Recent published work from my group demonstrated: (1) mitochondrial division is chronically enhanced in RAS-transformed murine cells and human cancer lines harboring mutations within the MAPK pathway, (2) the mitochondrial division machinery is essential for cellular transformation, (3) targeted therapies that inhibit oncogenic MAPK signaling turn off the mitochondrial division machinery, and (4) chronic mitochondrial division is sufficient to initiate mitochondrial dysfunction and cancer cell metabolism. For decades, the presence of mtDNA mutations and mitochondrial dysfunction in cancer has been described, but the molecular mechanisms that drive these changes and their impact on cancer biology remain speculative. While others and we identified that mitochondrial division is requisite to cancer-associated mitochondrial dysfunction and is targeted by oncogenic MAPK pathway inhibitors, the molecular mechanisms linking mitochondrial division, mitochondrial dysfunction, and cancer cell survival are poorly understood. We hypothesize that oncogenic MAPK signaling induces chronic mitochondrial fragmentation, which supports mutation of the mitochondrial genome and subsequent functional heterogeneity within the mitochondrial network. This project emerged following years of effort to identify how mitochondrial division contributes to cancer biology, and we propose three complementary specific aims. Aim 1: Establish that chronic mitochondrial division is responsible for cancer-associated mtDNA mutations and subsequent mitochondrial dysfunction in melanocytes. Aim 2: Demonstrate that chronic mitochondrial division induced mtDNA mutations link mitochondrial heterogeneity, tumorigenic potential, and metabolic plasticity. Aim 3: Reveal the broad requirement for chronic mitochondrial division in oncogenic transformation of cells and tissues. These aims will be achieved by using next-generation mtDNA sequencing, state-of-the-art mitochondrial function assays, and metabolomics approaches. Together, the results of this application will reveal that: (1) chronic mitochondrial division is permissive for mtDNA mutations, mitochondrial dysfunction, and tumorigenesis; and (2) proof-of- concept evidence that pharmacologically targeting chronic mitochondrial division may provide therapeutic potential to prevent and treat cancer.