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Modeling Ca2+ signals: understanding Ca2+ regulatory networks in cells - Ca2+ stores: mitochondria, models of spatially non-uniform Ca2+ signals, applications to analysis of experimental results

Part 3 of 3
Published on August 31, 2021   49 min

A selection of talks on Cell Biology

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We now consider the case where calcium-sensitive calcium channels operate in a store that maintains a driving force favoring calcium uptake instead of release. This case is relevant to mitochondria, another major organelle found in Eukaryotic cells. Mitochondria maintain a large electrical potential difference across their inner membrane, with the internal voltage being 150 to 200 millivolts lower than the extramitochondrial or cytosolic voltage. This voltage drop arises through the interplay between active proton export mediated by pumps that are part of the electron transport chain. Passive proton re-entry via the ATP synthase, which is coupled to ATP synthesis. The inner membrane is also the site of a calcium-permeable channel called the mitochondrial uniporter where MCU-like ryanodine receptors, MCU channels open in response to elevations in the cytosolic calcium concentration and are permeable to calcium. However, unlike ryanodine receptors, when these channels open, they normally mediate the flow of calcium into the organelle down at a steep electrochemical gradient, mainly due to the large voltage drop across the inner membrane. The symbolize approach to modeling mitochondrial calcium handling and its effect on stimulus evoke calcium responses is to represent mitochondria as a compartment within the cytosol exposed to a spatially uniform cytosolic calcium concentration. As with the description of the ER, this one pool description of mitochondria lumps together the effects of a distributed organelle system into a single equivalent pool. Passive calcium movements across the inner membrane are controlled by MCU channels and occur at a rate that can be described as the product of two terms, K uni, which increases with the calcium concentration and the cytosolic calcium concentration itself. As will be shown later, this description is an approximation based on the GHK flux equation, where the K uni lumps together the calcium-dependent permeability of the inner membrane and the electrical driving force on calcium. More general rate laws can be devised, but the simple one used here will suffice for giving us a feeling for the way mitochondrial calcium transport influences cellular calcium dynamics. There is one more transport pathway. We must consider the efflux pathway by which mitochondria release calcium, the main efflux pathway, and neurons because a sodium-calcium exchanger or NC x, which releases calcium coupled to sodium entry at a rate that depends saturable on the intro mitochondrial calcium concentration and the cytosolic sodium level. Because the exchange is electrogenic, transport also depends on the mitochondrial membrane potential. But since we assume the memory potential is constant, the voltage will not be explicitly expressed in the right description because the flux is directed into the cytosol, our sign convention requires that the flux mediated by NCI is negative. We now have a description of the net calcium flux between mitochondria and the cytosol. It's the sum of J uni and J naca. It is the net calcium flux that determines on a moment-to-moment basis, the direction of net calcium transport between the mitochondria and the cytosol and whether mitochondria act as a calcium source or sink. Note that the model does not include a description of the dynamics of sodium concentration and mitochondrial membrane potential. This would require introducing two more dependent variables which the viewer may consider doing later as an exercise.
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Modeling Ca2+ signals: understanding Ca2+ regulatory networks in cells - Ca2+ stores: mitochondria, models of spatially non-uniform Ca2+ signals, applications to analysis of experimental results

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