Ten years ago, the prevalent view of cellular calcium homeostasis was very simple and modeled after the sodium transport scheme. It was accepted that the cytoplasmic calcium activity was low, around 10−6 M, that calcium influx occurs passively down its electrochemical gradient and that calcium efflux is an uphill metabolically dependent process. The implications of this model is that calcium transport is controlled and regulated by the plasma membrane permeability on one hand and by the activity of the calcium pump on the other. Furthermore, the cytoplasmic calcium activity is primarily regulated by events occurring at the plasma membrane. However, in the course of our studies on calcium metabolism and calcium transport in isolated cells, it became obvious that this model was too simple. For instance we discovered an intracellular compartment which is kinetically distinct from the cytoplasmic calcium pool. The magnitude of this compartment can increase or decrease and its calcium turnover rise and fall independently from the cytoplasmic calcium and from the calcium transport across the plasma membrane. On every available evidence, this compartment represents a calcium pool in the cell mitochondria. Then we asked ourselves the following question: Does this mitochondria) calcium pool passively reflect the fluctuations occurring in the cytoplasm and at the plasma membrane? Or, to the contrary, do mitochondria control and regulate cytoplasmic calcium activity and the cell calcium metabolism including calcium transport? Several observations suggested to us that the second possibility was more likely: First, the changes in this compartment often preceded any other cellular effects; and second, the magnitude of the changes was always greater than all other observed alterations. In addition, the calcium transport velocity and capacity of mitochondria is much larger than that of the plasma membrane, and the surface area of the mitochondria inner membrane is 30 to 100 times greater than the plasma membrane surface. Open image in new window Figure 1. Model of cellular calcium distribution and exchange.