Brain mitochondrial calcium transport: Origins of the set-point concept and its application to physiology and pathology

The transport of calcium across the inner mitochondrial membrane plays a key role in neuronal physiology and pathology. The kinetic responses of the uniporter and efflux pathways are such that a cytosolic free calcium 'set-point' can be established - above which there is net calcium accumulation into the matrix that is reversed when plasma membrane transport lowers cytosolic calcium. Pathological activation of N-methyl-d-aspartate receptor mediated sodium and calcium entry into the neuron, as occurs in stroke and spreading depression, places severe demands on both the ATP-generating and calcium loading capacities of the neuronal mitochondria as the set-point is exceeded. Experiments that led to the concept of the set-point are reviewed.