Mechanisms of Mitochondrial Ultrastructural Changes and Metabolic Dysfunction Caused by Calcium Overload

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Project Summary/Abstract: Myocardial ischemia/reperfusion (IR) is an injury preceded by mitochondrial dysfunction caused by calcium overload. While mitochondrial calcium dynamics and molecular pathways have been extensively studied, little is known on how mitochondria accumulate and store calcium and how calcium overload effects mitochondrial function. This is significant since the main cause of cardiac tissue and cell death after a myocardial infarction is mediated by mitochondrial calcium overload. As there are no adequate treatments available, the nature of calcium storage and its impact on mitochondrial function requires further study. Herein, we show preliminary results that reveal an unprecedented link between cristae structure and mitochondrial function during calcium overload. The presented data suggest that preserving cristae during calcium overload confer protection against calcium overload. Confirming this hypothesis will add an exciting new therapeutic approach and puts in immediate play proteins not considered as drug targets to treat IR injury. The objectives of this proposal are 1) to characterize and quantify the calcium sequestration system and the direct effects on mitochondrial function, 2) to determine the functional impact of cristae remodeling in mitochondria ultrastructure associated with calcium overload, and 3) establish how known modulators of the calcium sequestration system alter mitochondrial function. The experimental approach in this proposal will use recent methods of advanced cryo- EM, spectrofluorimetry, ex vivo heart perfusion system, and high-resolution respirometry. Bioenergetic and functional data will be measured from isolated cardiac mitochondria from healthy, ischemic, and IR injured guinea pig hearts. In addition, support from this fellowship will be directed to acquire experimental and academic skills sets that are key to the proposal success. These will be approached by taking high-quality courses offered at MSU, hands-on training, workshops, and regional and national conferences. Gathering scientific expertise via the F31 Award in mitochondria and cellular physiology will provide opportunities for improving scientific communication through talks, posters, and manuscript writing. The opportunity granted via the F31 Award will continue and expand this work to encompass the bioenergetic consequences between mitochondrial calcium overload and mitochondrial ultrastructure related to a pathophysiological scenario such as IR injury. The combined efforts of the fellowship award, extensive expertise of sponsors, co-sponsors, collaborator, and the institution’s commitment to excellence is an optimal pathway to independence that will help unlock the potential as a successful scientist.