11.2.3.10: 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 (\(\Delta\)n_Ca²⁺ = -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, V_max, 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