A biophysically based mathematical model for the kinetics of mitochondrial calcium uniporter.
Ca2+ transport through mitochondrial Ca2+ uniporter is the primary Ca2+ uptake mechanism in respiring mitochondria. Thus, the uniporter plays a key role in regulating mitochondrial Ca2+. Despite the importance of mitochondrial Ca2+ to metabolic regulation and mitochondrial function, and to cell physiology and pathophysiology, the structure and composition of the uniporter functional unit and kinetic mechanisms associated with Ca2+ transport into mitochondria are still not well understood. In this study, based on available experimental data on the kinetics of Ca2+ transport via the uniporter, a mechanistic kinetic model of the uniporter is introduced. The model is thermodynamically balanced and satisfactorily describes a large number of independent data sets in the literature on initial or pseudo-steady-state influx rates of Ca2+ via the uniporter measured under a wide range of experimental conditions. The model is derived assuming a multi-state catalytic binding and Eyring's free-energy barrier theory-based transformation mechanisms associated with the carrier-mediated facilitated transport and electrodiffusion. The model is a great improvement over the previous theoretical models of mitochondrial Ca2+ uniporter in the literature in that it is thermodynamically balanced and matches a large number of independently published data sets on mitochondrial Ca2+ uptake. This theoretical model will be critical in developing mechanistic, integrated models of mitochondrial Ca2+ handling and bioenergetics which can be helpful in understanding the mechanisms by which Ca2+ plays a role in mediating signaling pathways and modulating mitochondrial energy metabolism.
Dash
Ranjan K
RK
Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Qi
Feng
F
Beard
Daniel A
DA
D000465:Algorithms; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D051381:Rats; D015398:Signal Transduction; D013816:Thermodynamics
D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D002118:Calcium