Na + ‐dependent regulation of extramitochondrial Ca 2+ by rat‐liver mitochondria

The presence and significance of Na + ‐induced Ca 2+ release from rat liver mitochondria was investigated by the arsenazo technique. Under the experimental conditions used, the mitochondria, as expected, avidly extracted Ca 2+ from the medium. However, when the uptake pathway was blocked with ruthenium red, only a small rate of ‘basal’ release of Ca 2+ was seen (0.3 nmol Ca 2+ × min −1 × mg −1 ), in marked contrast to earlier reports on a rapid loss of sequestered Ca 2+ from rat liver mitochondria. The addition of Na + in ‘cytosolic’ levels (20 mM) led to an increase in the release rate by about 1 nmol Ca 2+ × min −1 × mg −1 . This effect was specific for Na + . The significance of this Na + ‐induced Ca 2+ release, in relation to the Ca 2+ uptake mechanism, was investigated (in the absence of uptake inhibitors) by following the change in the extramitochondrial Ca 2+ steady‐state level (set point) induced by Na + . A five‐fold increase in this level, from less than 0.2 μM to more than 1 μM, was induced by less than 20 mM Na + . The presence of K + increased the sensitivity of the Ca 2+ homeostat to Na + . The effect of Na + on the extramitochondrial level was equally well observed in an K + /organic‐anion buffer as in a sucrose buffer. Liver mitochondria incubated under these circumstances actively counteracted a Ca 2+ or EGTA challenge by taking up or releasing Ca 2+ , so that the initial level, as well as the Na + ‐controlled level, was regained. It was concluded that liver mitochondria should be considered Na + ‐sensitive, that the capacity of the Na + ‐induced efflux pathway was of sufficient magnitude to enable it to influence the extramitochondrial Ca 2+ level biochemically and probably also physiologically, and that the mitochondria have the potential to act as active, Na + ‐dependent regulators of extramitochondrial (‘cytosolic’) Ca 2+ . It is suggested that changes of cytosolic Na + could be a mediator between certain hormonal signals (notably α 1 ‐adrenergic) and changes in this extramitochondrial (‘cytosolic’) Ca 2+ steady state level.