Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells

Mitochondrial Ca2+ transport was initially considered important only in buffering of cytosolic Ca2+ by acting as a “sink” under conditions of Ca2+ overload. The main regulator of ATP production was considered to be the relative concentrations of high energy phosphates. However, work by Denton and McCormack in the 1970s and 1980s showed that free intramitochondrial Ca2+ ([Ca2+]m) activated dehydrogenase enzymes in mitochondria, leading to increased NADH and hence ATP production. This leads them to propose a scheme, subsequently termed a “parallel activation model” whereby increases in energy demand, such as hormonal stimulation or increased workload in muscle, produced an increase in cytosolic [Ca2+] that was relayed by the mitochondrial Ca2+ transporters into the matrix to give an increase in [Ca2+]m. This then stimulated energy production to meet the increased energy demand. With the development of methods for measuring [Ca2+]m in living cells that proved [Ca2+]m changed over a dynamic physiological range rather than simply soaking up excess cytosolic [Ca2+], this model has now gained widespread acceptance. However, work by ourselves and others using targeted probes to measure changes in both [Ca2+] and [ATP] in different cell compartments has revealed variations in the interrelationships between these two in different tissues, suggesting that metabolic regulation by Ca2+ is finely tuned to the demands and function of the individual organ.