Mitochondrial Ca2+ Transport in Heart Cells

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The long-term objective of our research is to elucidate mechanisms of mitochondrial Ca2+ transport in cardiac muscle cells under both physiological and pathological conditions. Extensive studies have implicated that mitochondrial Ca2+ play a pivotal role in controlling cellular Ca2+ homeostasis, energy metabolism, and apoptosis. However, little is known about the molecular identities and functional diversities of mitochondrial Ca2+ transporters. Our Central hypothesis is that "cardiac mitochondria contain at least two Ca2+-activated influx mechanisms, a mitochondrial ryanodine receptor that operates most effectively in the lower ranges (<50 ^M) of Ca2+ and a Ca2+ uniporter that operates most effectively in higher ranges of Ca2+. These two Ca2+ transporters sequester Ca2+ proficiently and complementarity for regulating Ca2+ homeostasis, ATP production, and reactive oxygen species generation. These mitochondrial Ca2+- mediated functions are achieved physiologically by a concomitant increase in mitochondrial ADP, serving not only as a substrate for ATP production but also an inhibitor for mitochondrial permeability transition pores. In diseased states, this coordinated interaction between Ca2+ and ADP is disrupted and prone the cells to Ca2+- and oxidative stress-mediated injury and death". The four specific aims are: 1) to further characterize the molecular properties of mitochondrial ryanodine receptor, 2) to evaluate the distinct role of mitochondrial ryanodine receptor and Ca2+ uniporter in Ca2+ regulation, 3) to determine the modulation of mitochondrial Ca2+ uptake by redox environments, and 4) to elucidate the role of mitochondrial Ca2+ and ADP in balancing cellular ATP generation and Ca2+ homeostasis in healthy and cardiomyopathic hearts. Working closely with our collaborators, we will use multidisciplinary approaches encompassing cell biology, biochemistry, biophysics, and molecular biology, to elucidate the molecular and functional characteristicsof mitochondrial Ca2+ influx mechanisms. Recent studies of diseases caused by either mitochondrial DNA mutations or mitochondrial dysfunction all suggest that Ca2+ deregulation is most critical. Some examples of such diseases are cardiomyopthy in chronic heart failure, ischemic heart disease, neurodegenerative diseases, diabetics, obesity, and aging. Therefore, completion of our research aims will not only to have a significant impact on our understanding of basic mechanisms in the etiology of mitochondria-mediated diseases, but also on our strategies in developing the therapeutic means for treating these diseases.