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Proteomic Analyses of Mitochondrial Biogenesis and Biochemistry

David Pagliarini

Appointment Period: 2009-2009 / Grant Year: [25]

David PagliariniMy research addresses a fundamental metabolic transformation seen in nearly every tumor type. Known as the "Warburg Effect", this phenomenon involves a switch away from oxygen-dependent energy production toward a more rapid and inefficient system termed glycolysis. At the heart of this transformation is the suppression of mitochondria, the subcellular organelles that drive the bulk of energy production in most healthy cell types. In rapidly growing tumors, mitochondrial content and metabolism are diminished, however the cellular mechanisms for accomplishing this are largely unknown.

My work as a postdoctoral fellow has focused on understanding mitochondrial composition and on the cellular mechanisms that drive the production of these organelles. In particular, I've investigated the impact of oxygen and nutrient deprivation-conditions often present in tumor microenvironments-on mitochondrial biogenesis. Using state-of-the-art proteomics technology, I've helped discover that cellular iron levels are critical to this process, and that iron sequestration leads to rapid loss of mitochondrial machinery. My results provide insight into the physiological conditions that might underlie the how tumor switch their metabolism, and frames a strategy to exploit the biochemical differences between cancerous and healthy cells.

My affiliation with the Growth Regulation & Oncogenesis Training Grant program has been instrumental in guiding my experimental approaches to outstanding challenges in cancer research. In addition to the monetary support, the community of trainees and advisors has helped me to think more globally about cancer paradigms and has helped me to understand how my work fits into the larger framework of cancer research.

Doughty-Shenton D, Joseph JD, Zhang J, Pagliarini DJ, Kim Y, Lu D, Dixon JE, Casey PJ. Pharmacological targeting of the mitochondrial phosphatase PTPMT1. J Pharmacol Exp Ther. (2010) 333:584-92. PMID: 20167843; PMCID: PMC2872949.

Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci USA. (2009) 106:7507-12PMID: 19372376; PMCID: PMC2669787.