Calcium and bicarbonate signaling control mitochondrial ATP production

Two unexpected findings surfaced from a recent careful investigation of ATP production by cardiac mitochondria. First, the Ca2+ sensitivity of ATP production under physiological conditions involved neither direct Ca2+-sensitivity of Krebs cycle enzymes nor Ca2+-sensitivity of the electron transport chain proteins. Instead the Ca2+ sensitivity came from the matrix proteins pyruvate dehydrogenase and glutamate dehydrogenase. Second, only half of the dynamic range of ATP production could be attributed to changes in matrix [Ca2+]m. Here we report on the huge contribution to ATP production of an unlikely source -- the consumption of energy substrates. This contribution occurs as high-energy substrates are metabolized by mitochondria and eventually oxidized to CO2. We show that it is the water-soluble CO2 equilibrium-product, bicarbonate (HCO3-), that regulates the second half of physiological ATP production. This regulation is shown to occur through soluble adenylyl cyclase (sAC) which is directly activated by bicarbonate to locally produce the second messenger cAMP. Additionally, we show that the sAC signalling occurs within the mitochondria intermembrane space where its activation leads to the augmentation of ATP production. This signaling arm of the cardiac mitochondrial ATP production machinery is also shown to work in conjunction with [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease.