The interplay of mitochondria with calcium: An historical appraisal

Indirect findings in the 1950s had indicated that mitochondria could accumulate Ca2+, but only in 1961 isolated mitochondria were directly shown to take it up in a process driven by the activity of the respiratory chain or by the hydrolysis of added ATP. The uptake of Ca2+ could be accompanied by the simultaneous uptake of inorganic phosphate, leading to the precipitation of hydroxyapatite in the matrix and to the effective buffering of the free Ca2+ concentration in it. The uptake of Ca2+ occurred via an electrophoretic uniporter that has been molecularly identified only recently. Ca2+ was then released through a Na+/Ca2+ exchanger that has also been identified very recently (a H+/Ca2+ antiporter has also been described in some mitochondrial types). In the matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated by Ca2+, providing a rationale for the Ca2+ cycling process. The affinity of the uptake uniporter was found to be too low to efficiently regulate Ca2+ in the low to mid nM concentration in the cytosol. However, a number of findings showed that energy linked transport of Ca2+ did nevertheless occur in mitochondria in situ. The enigma was solved in the 1990s, when it was found that perimitochondrial Ca2+ pools are created by the discharge of Ca2+ from vicinal endoplasmic reticulum stores in which the concentration of Ca2+ is high enough to satisfy the poor affinity of the uniporter. Thus, mitochondria have now regained a key role in the regulation of cytosolic Ca2+ (not only of their own internal Ca2+).