A Minimal Model for the Mitochondrial Rapid Mode of Ca(2+) Uptake Mechanism

Mitochondria possess a remarkable ability to rapidly accumulate and sequester Ca(2+). One of the mechanisms responsible for this ability is believed to be the rapid mode (RaM) of Ca(2+) uptake. Despite the existence of many models of mitochondrial Ca(2+) dynamics, very few consider RaM as a potential mechanism that regulates mitochondrial Ca(2+) dynamics. To fill this gap, a novel mathematical model of the RaM mechanism is developed herein. The model is able to simulate the available experimental data of rapid Ca(2+) uptake in isolated mitochondria from both chicken heart and rat liver tissues with good fidelity. The mechanism is based on Ca(2+) binding to an external trigger site(s) and initiating a brief transient of high Ca(2+) conductivity. It then quickly switches to an inhibited, zero-conductive state until the external Ca(2+) level is dropped below a critical value (∼100–150 nM). RaM's Ca(2+)- and time-dependent properties make it a unique Ca(2+) transporter that may be an important means by which mitochondria take up Ca(2+) in situ and help enable mitochondria to decode cytosolic Ca(2+) signals. Integrating the developed RaM model into existing models of mitochondrial Ca(2+) dynamics will help elucidate the physiological role that this unique mechanism plays in mitochondrial Ca(2+)-homeostasis and bioenergetics.