Calcium Movement in Cardiac Mitochondria |
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Authors: | Liron Boyman Aristide C Chikando George SB Williams Ramzi J Khairallah Sarah Kettlewell Christopher W Ward Godfrey L Smith Joseph PY Kao W Jonathan Lederer |
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Institution: | 1 Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland;2 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland;3 University of Maryland School of Nursing, Baltimore, Maryland;4 School of Systems Biology, George Mason University, Fairfax, Virginia;5 Institute of Cardiovascular and Medical Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;6 Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, Illinois |
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Abstract: | Existing theory suggests that mitochondria act as significant, dynamic buffers of cytosolic calcium (Ca2+]i) in heart. These buffers can remove up to one-third of the Ca2+ that enters the cytosol during the Ca2+]i transients that underlie contractions. However, few quantitative experiments have been presented to test this hypothesis. Here, we investigate the influence of Ca2+ movement across the inner mitochondrial membrane during both subcellular and global cellular cytosolic Ca2+ signals (i.e., Ca2+ sparks and Ca2+]i transients, respectively) in isolated rat cardiomyocytes. By rapidly turning off the mitochondria using depolarization of the inner mitochondrial membrane potential (ΔΨm), the role of the mitochondria in buffering cytosolic Ca2+ signals was investigated. We show here that rapid loss of ΔΨm leads to no significant changes in cytosolic Ca2+ signals. Second, we make direct measurements of mitochondrial Ca2+] (Ca2+]m) using a mitochondrially targeted Ca2+ probe (MityCam) and these data suggest that Ca2+]m is near the Ca2+]i level (∼100 nM) under quiescent conditions. These two findings indicate that although the mitochondrial matrix is fully buffer-capable under quiescent conditions, it does not function as a significant dynamic buffer during physiological Ca2+ signaling. Finally, quantitative analysis using a computational model of mitochondrial Ca2+ cycling suggests that mitochondrial Ca2+ uptake would need to be at least ∼100-fold greater than the current estimates of Ca2+ influx for mitochondria to influence measurably cytosolic Ca2+] signals under physiological conditions. Combined, these experiments and computational investigations show that mitochondrial Ca2+ uptake does not significantly alter cytosolic Ca2+ signals under normal conditions and indicates that mitochondria do not act as important dynamic buffers of Ca2+]i under physiological conditions in heart. |
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