The regulatory role of mitochondria in capacitative calcium entry.
Mitochondria can uptake calcium by using a uniport in the mitochondrial inner membrane. This uniport is driven by the membrane potential. The uniport has a low affinity for calcium. This implies that mitochondria are not able to take up calcium very efficiently. It is observed, however, that mitochondria do take up calcium and this happens more efficiently than one would expect based on the low affinity of the uniport. This can be explained by the discovery that locally there can be high concentrations of calcium (much higher than the global concentration of calcium in the cytoplasm) which enables the mitochondria to efficiently uptake calcium. Local high concentrations of calcium appear close to calcium channels in the endoplasmic reticulum (ER) and the plasma membrane (PM).
The ER is the cell's biggest calcium store and the calcium concentration in the ER can be 3-4 orders of magnitude larger than the concentration in the cytosol. The opening of calcium channels in the ER, which enables calcium to passively flow into the cytosol, depends on the concentration of calcium in the cytosol ([Cacyt]). A higher [Cacyt] induces the opening of the calcium channels in the ER. This positive feedback system is called Calcium-Induced Calcium Release (CICR). If the [Cacyt] rises above a certain value, however, there is a negative feedback on IP_3-receptor calcium channels (which let calcium flow from the ER into the cytoplasm). This negative feedback inhibits the release of calcium from the ER and consequently decreases the capacitative calcium entry (CCE). This eventually stops the calcium signal in the cell.
Mitochondria in the vicinity of calcium channels of the ER will take up calcium. This lowers the local [Cacyt] and can prevent the [Cacyt] from reaching the level at which it starts to give negative feedback to calcium channels in the ER. Mitochondria can therefore inhibit negative feedback on IP_3-receptor calcium channels. This stimulates the depletion of calcium stores and also stimulates CCE.
A concentration of calcium in the mitochondrial matrix that is too high can lead to damaged mitochondrial function consequently stops mitochondrial calcium uptake. This will lead to an increase in [Cacyt] and this stimulates negative feedback to the calcium channels. By forming mitochondrial networks, the concentration of calcium inside the mitochondria can be kept at a lower level since the calcium will spread throughout the network. This means that more calcium can be taken up by the mitochondria and less negative feedback will be given to the calcium channels. The formation of mitochondrial networks can therefore lead to a longer effectiveness of the calcium signal.
A concentration of calcium in the mitochondrial matrix that is too high can lead to damaged mitochondrial function consequently stops mitochondrial calcium uptake. This will lead to an increase in [Cacyt] and this stimulates negative feedback to the calcium channels. By forming mitochondrial networks, the concentration of calcium inside the mitochondria can be kept at a lower level since the calcium will spread throughout the network. This means that more calcium can be taken up by the mitochondria and less negative feedback will be given to the calcium channels. The formation of mitochondrial networks can therefore lead to a longer effectiveness of the calcium signal.
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