Abstract
Mitochondria possess a remarkable ability to rapidly accumulate and sequester Ca2+. One of the mechanisms responsible for this ability is believed to be the rapid mode (RaM) of Ca2+ uptake. Despite the existence of many models of mitochondrial Ca2+ dynamics, very few consider RaM as a potential mechanism that regulates mitochondrial Ca2+ 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 Ca2+ uptake in isolated mitochondria from both chicken heart and rat liver tissues with good fidelity. The mechanism is based on Ca2+ binding to an external trigger site(s) and initiating a brief transient of high Ca2+ conductivity. It then quickly switches to an inhibited, zero-conductive state until the external Ca2+ level is dropped below a critical value (∼100–150 nM). RaM's Ca2+- and time-dependent properties make it a unique Ca2+ transporter that may be an important means by which mitochondria take up Ca2+ in situ and help enable mitochondria to decode cytosolic Ca2+ signals. Integrating the developed RaM model into existing models of mitochondrial Ca2+ dynamics will help elucidate the physiological role that this unique mechanism plays in mitochondrial Ca2+-homeostasis and bioenergetics.
Highlights
Calcium plays many key roles with respect to mitochondrial bioenergetics [1,2,3]
Recent findings have expanded this list of Ca2+ transport mechanisms to include the rapid mode (RaM) of Ca2+ uptake and the mitochondrial ryanodine receptor [14,15,16]
It is quite remarkable that the simple 4-state RaM model captured the salient features of RaM identified in the available experimental data sets for both heart and liver tissues
Summary
Calcium plays many key roles with respect to mitochondrial bioenergetics [1,2,3]. The currently accepted paradigm is that Ca2+directly modulates mitochondrial NADH levels via allosteric activation of matrix dehydrogenases [4,5,6,7], enhances ATP production via F1FO -ATPase activation [8,9], as well as, triggers a catastrophic phenomenon known as mitochondrial permeability transition [10,11,12]. The general consensus is that a highly-selective, high-conductance Ca2+ channel, the Ca2+ uniporter (CU), accommodates Ca2+ entry while the combined action of an nH+/Ca2+ and an nNa+/Ca2+ exchanger facilitate Ca2+ removal from the mitochondrial matrix [13]. Recent findings have expanded this list of Ca2+ transport mechanisms to include the rapid mode (RaM) of Ca2+ uptake and the mitochondrial ryanodine receptor [14,15,16]. These two additional uptake mechanisms have been proposed to be alternative conformational states of the CU [3,17], and quite possibly the permeability transition pore [13]. It is strongly believed that the CU has been identified (MICU1) [20], more conclusive evidence will be necessary to demonstrate its true identity and connect it to the Ca2+
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