title: Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptake.
abstract: Cardiac mitochondria can act as a significant Ca(2+) sink and shape cytosolic Ca(2+) signals affecting various cellular processes, such as energy metabolism and excitation-contraction coupling. However, different mitochondrial Ca(2+) uptake mechanisms are still not well understood. In this study, we analysed recently published Ca(2+) uptake experiments performed on isolated guinea pig cardiac mitochondria using a computer model of mitochondrial bioenergetics and cation handling. The model analyses of the data suggest that the majority of mitochondrial Ca(2+) uptake, at physiological levels of cytosolic Ca(2+) and Mg(2+), occurs through a fast Ca(2+) uptake pathway, which is neither the Ca(2+) uniporter nor the rapid mode of Ca(2+) uptake. This fast Ca(2+) uptake component was explained by including a biophysical model of the ryanodine receptor (RyR) in the computer model. However, the Mg(2+)-dependent enhancement of the RyR adaptation was not evident in this RyR-type channel, in contrast to that of cardiac sarcoplasmic reticulum RyR. The extended computer model is corroborated by simulating an independent experimental dataset, featuring mitochondrial Ca(2+) uptake, egress and sequestration. The model analyses of the two datasets validate the existence of two classes of Ca(2+) buffers that comprise the mitochondrial Ca(2+) sequestration system. The modelling study further indicates that the Ca(2+) buffers respond differentially depending on the source of Ca(2+) uptake. In particular, it suggests that the Class 1 Ca(2+) buffering capacity is auto-regulated by the rate at which Ca(2+) is taken up by mitochondria.
authors.affiliation: Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-6509, USA. rdash@mcw.edu.
authors.forename: Shivendra G
authors.initials: SG
authors.lastname: Tewari
authors.forename: Amadou K S
authors.initials: AK
authors.lastname: Camara
authors.forename: David F
authors.initials: DF
authors.lastname: Stowe
authors.forename: Ranjan K
authors.initials: RK
authors.lastname: Dash
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods*; D004734:Energy Metabolism / Q000502:physiology*; D005544:Forecasting; D006168:Guinea Pigs; D008929:Mitochondria, Heart / Q000378:metabolism*; D008962:Models, Theoretical
chemical_list: D002118:Calcium