# 3.10: Mitochondrial Calcium Ion Transport


## Influx

Mitochondria isolated from various types of animal cells—but, interestingly, not those from plant cells—can rapidly accumulate exogenous Ca2+.59 The transporter is located in the inner membrane and the driving force behind the Ca2+ transport appears to be merely the high potential difference across this membrane ($$\Delta \Psi$$ ≈ 150 to 180 mV, negative in the inner matrix). This potential difference is fairly closely maintained by the pumping out of H+ from the matrix by cell respiration. For the transport of 1 mol Ca2+ from the "outside" (= cytoplasm) to the "inside" (= inner mitchondrial matrix), we may deduce from Equation (3.4) that the free-energy change $$\Delta$$G may be written ($$\Delta$$nCa2+ = -1)

$\Delta G = - RT \cdotp ln\frac{[Ca^{2+}]_{o}}{[Ca^{2+}]_{i}} - 2F \Delta \Psi \ldotp \tag{3.11}$

From this analysis it may be inferred that the limiting Ca2+ concentration (or activity) ratio that can be achieved by this electrogenic pump (i.e., $$\Delta$$G = 0) is

$\dfrac{[Ca^{2+}]_{o}}{[Ca^{2+}]_{i}} = e^{\frac{-2 F \Delta \Psi}{RT}} \tag{3.12}$

With $$\Delta \Psi$$ = 150 mV, this ratio is calculated to be 8.4 x 10-6 at 25 °C. It is evident that, as long as the Ca2+ influx would not lower the membrane potential difference, the Ca2+ uniporter has a very high pumping potential. Measured values of the pumping rate, Vmax, are indeed high (>10 nmol/mg protein59) and probably limited only by the rate of electron transport and H+ extrusion in the mitochondria.

Mitochondria may accumulate large quantities of Ca2+, probably to maintain electroneutrality. To prevent the buildup of high concentrations of free Ca2+ (and of osmotic pressure), phosphate ions are also transported into the inner matrix, where an amorphous calcium phosphate—or possibly a phosphocitrate60—is formed. The equilibrium concentration of free Ca2+ in the mitochondrial matrix may as a result be comparatively low, on the order of 1 $$\mu$$M.

The molecular nature of the mitochondrial Ca2+ uniporter continues to be elusive, and needs to be studied further.

## Efflux

Mitochondria, as well as SR, release Ca2+ ions by mechanisms other than "back leakage" through the pumps. In mitochondria from excitable cells, the efflux occurs mainly through an antiport, where 2 Na+ ions are transported inward for every Ca2+ ion departing for the cytosolic compartment.61 In other cells there is evidence for the dominance of a 2H+-Ca2+ antiport.59 In all likelihood the Ca2+ efflux is regulated, possibly by the redox state of pyridine nucleotides in the mitochondria. As with the Ca2+ uniporter, few details on the molecular nature of the antiporters are presently available.

## Ca2+ Efflux from Non-mitrochondrial Stores

Release of Ca2+ from ER and SR presently appears to be the prime effect of the new intracellular messenger 1,4,5-triphosphoinositol (1,4,5-IP3) released into the cytoplasm as a result of an external hormonal stimulus (see Section IV.C). It seems that receptors for 1,4,5-IP3 have been established on ER, and that the binding of 1,4,5-IP3 causes a release of Ca2+ stored in this organelle.62,63,170,171 In addition to the receptor-controlled Ca2+ efflux, there may be other pathways for Ca2+ release, and Ca2+ mobilization may be regulated by other intracellular entities, the Ca2+ ions themselves included.

## Other Voltage-gated or Receptor-activated Ca2+ Channels

In addition to the transport pathways already discussed, some cells seem to have Ca2+ channels in the plasma membrane that can be opened by the action of an agonist on a receptor or that are gated in response to changes in membrane potential.64 For example, Ca2+ channels can be opened by nicotinic cholinergic agonists65 or by the excitatory amino acid N-methyl-D-aspartate (NMDA).66 Endochrine cells and also some muscle and neuronal cells have voltage-sensitive Ca2+ channels.67,68 We will not discuss these further, but merely point to their existence. We finally note that during the last few years knowledge about the mechanisms of Ca2+ entry and release to and from extracellular and intracellular pools has increased dramatically, and we refer the reader to recent reviews of the field.175,176

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