Molecular insights into the regulation of mitochondrial calcium uptake

Project Summary/Abstract Heart failure is the leading cause of death in the United States and represents a major burden on the US healthcare system. Mitochondrial dysfunction and disruption of cellular energetics are heavily implicated in the pathogenesis of heart disease. A key regulator of mitochondrial function is Ca2+ uptake through the mitochondrial calcium uniporter complex (“the uniporter”). The uniporter regulates cytosolic Ca2+ transients, oxidative phosphorylation, and cell death pathways. However, the molecular mechanisms that control uniporter activation are not well resolved. Further insight into how the uniporter is regulated would increase our understanding of mitochondrial Ca2+ signaling and inform the development of therapeutics aimed at modulating uniporter activity. The Research Training Plan involves using a multidisciplinary approach to investigate how key signaling molecules and regulatory factors control uniporter activity. Understanding the molecular mechanisms of the Ca2+- dependent regulation of the uniporter and elucidating a novel gating mechanism will produce a major advance in the field. The PI will receive comprehensive training to carry out structural, biophysical, biochemical, and functional studies on membrane transport proteins. The Career Development Plan is tailored to help the PI develop skills in experimental approaches, research design, project management, mentorship, and written and oral communication. The sponsor, together with the environment, offers strong support for the PI’s training and career development. In summary, completion of the strong Research Training Plan together with the Career Development Plan will help prepare the applicant for a career as an independent scientist. The proposed research will lead to significant advances in understanding mitochondrial Ca2+ uptake and will open potential avenues for therapeutic intervention in diseases involving aberrant mitochondrial Ca2+ signaling.