title: Coupling calcium dynamics and mitochondrial bioenergetic: an in silico study to simulate cardiomyocyte dysfunction.
abstract: The coupling of intracellular Ca(2+) dynamics with mitochondrial bioenergetic is crucial for the functioning of cardiomyocytes both in healthy and disease conditions. The pathophysiological signature of the Cardiomyocyte Dysfunction (CD) is commonly related to decreased ATP production due to mitochondrial functional impairment and to an increased mitochondrial calcium content ([Ca(2+)]m). These features advanced the therapeutic approaches which aim to reduce [Ca(2+)]m. But whether [Ca(2+)]m overload is the pathological trigger for CD or a physiological consequence, remained controversial. We addressed this issue in silico and showed that [Ca(2+)]m might not directly cause CD. Through model parameter recalibration, we demonstrated how mitochondria cope up with functionally impaired processes and consequently accumulate calcium. A strong coupling of the [Ca(2+)]m oscillations with the ATP synthesis rate ensures robust calcium cycling and avoids CD. We suggested a cardioprotective role of the mitochondrial calcium uniporter and predicted that a mitochondrial sodium calcium exchanger could be a potential therapeutic target to restore the normal functioning of the cardiomyocyte.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India.
authors.forename: Phonindra Nath
authors.initials: PN
authors.lastname: Das
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pedruzzi
authors.affiliation: Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata-700032, India.
authors.forename: Nandadulal
authors.initials: N
authors.lastname: Bairagi
authors.affiliation: Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad-121001, India. samat.chatterjee@thsti.res.in.
authors.forename: Samrat
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002138:Calibration; D003198:Computer Simulation; D004734:Energy Metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D035501:Uncertainty
chemical_list: D002118:Calcium