Abstract
Calcium is an important regulator of mitochondrial function. Since there can be tight coupling between inositol 1,4, 5-trisphosphate-sensitive Ca(2+) release and elevation of mitochondrial calcium concentration, we have investigated whether a similar relationship exists between the release of Ca(2+) from the ryanodine receptor and the elevation of mitochondrial Ca(2+). Perfusion of permeabilized A10 cells with inositol 1,4, 5-trisphosphate resulted in a large transient elevation of mitochondrial Ca(2+) to about 8 microm. The response was inhibited by heparin but not ryanodine. Perfusion of the cells with Ca(2+) buffers in excess of 1 microm leads to large increases in mitochondrial Ca(2+) that are much greater than the perfused Ca(2+). These increases, which average around 10 microm, are enhanced by caffeine and inhibited by ryanodine and depletion of the intracellular stores with either orthovanadate or thapsigargin. We conclude that Ca(2+)-induced Ca(2+) release at the ryanodine receptor generates microdomains of elevated Ca(2+) that are sensed by adjacent mitochondria. In addition to ryanodine-sensitive stores acting as a source of Ca(2+), Ca(2+)-induced Ca(2+) release is required to generate efficient elevation of mitochondrial Ca(2+).
Highlights
Mitochondrial ATP synthesis is vital to all but a few primitive eukaryotic cells, and Ca2ϩ has been shown to be a key regulator of mitochondrial function [1,2,3,4]
Since there can be tight coupling between inositol 1,4,5-trisphosphate-sensitive Ca2؉ release and elevation of mitochondrial calcium concentration, we have investigated whether a similar relationship exists between the release of Ca2؉ from the ryanodine receptor and the elevation of mitochondrial Ca2؉
We conclude that Ca2؉induced Ca2؉ release at the ryanodine receptor generates microdomains of elevated Ca2؉ that are sensed by adjacent mitochondria
Summary
Mitochondrial ATP synthesis is vital to all but a few primitive eukaryotic cells, and Ca2ϩ has been shown to be a key regulator of mitochondrial function [1,2,3,4]. Initial studies using targeted aequorin revealed rapid and large transient elevations of [Ca2ϩ]m in response to Gprotein-coupled agonists. Both the transient nature and the large amplitude of the [Ca2ϩ]m responses are explained by a hypothesis in which the mitochondria sense microdomains of highly elevated Ca2ϩ adjacent to the InsP3 release sites in the ER [7]. Our data point to Ca2ϩ release by both InsP3 and CICR as being mechanisms by which microdomains of elevated [Ca2ϩ]c are generated These microdomains act as a source of Ca2ϩ for large transient elevations of [Ca2ϩ]m
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