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.