The role of Ca(2+) signaling in the coordination of mitochondrial ATP production with cardiac work

Abstract

The heart is capable of balancing the rate of mitochondrial ATP production with utilization continuously over a wide range of activity. This results in a constant phosphorylation potential despite a large change in metabolite turnover. The molecular mechanisms responsible for generating this energy homeostasis are poorly understood. The best candidate for a cytosolic signaling molecule reflecting ATP hydrolysis is Ca(2+). Since Ca(2+) initiates and powers muscle contraction as well as serves as the primary substrate for SERCA, Ca(2+) is an ideal feed-forward signal for priming ATP production. With the sarcoplasmic reticulum to cytosolic Ca(2+) gradient near equilibrium with the free energy of ATP, cytosolic Ca(2+) release is exquisitely sensitive to the cellular energy state providing a feedback signal. Thus, Ca(2+) can serve as a feed-forward and feedback regulator of ATP production. Consistent with this notion is the correlation of cytosolic and mitochondrial Ca(2+) with work in numerous preparations as well as the localization of mitochondria near Ca(2+) release sites. How cytosolic Ca(2+) signaling might regulate oxidative phosphorylation is a focus of this review. The relevant Ca(2+) sensitive sites include several dehydrogenases and substrate transporters together with a post-translational modification of F1-FO-ATPase and cytochrome oxidase. Thus, Ca(2+) apparently activates both the generation of the mitochondrial membrane potential as well as utilization to produce ATP. This balanced activation extends the energy homeostasis observed in the cytosol into the mitochondria matrix in the never resting heart.

Figure 1

Effect of pacing workload on the ³¹P NMR detected high energy phosphates in the canine heart in vivo. The post spectrum was collected after a pacing that increased the rate pressure product by ∼2 fold. Data adapted from Heineman and Balaban [61]

Figure 2

Estimated relative contributions of heart rate, contractility and Starling relationship to the overall increase in myocardial oxygen consumption associated with exercise. Data adapted from [45].

Figure 3

Correlation of peak systolic Ca²⁺ levels and oxygen consumption in the perfused rat heart. Heart work was increased using a combination of inotropic agents. Data adapted from [142].

Figure 4

Summary of the six Ca²⁺ regulatory sites in the heart mitochondria. The seven sites, outlined in white, are 1) F1-FO-ATPase, 2) APC, 3) Aralar/Citrin, 4) PDH, 5)ICDH, 6) αKDH and 7) COX. Of these sites COX is the least studied. Cit: Citrate. ICit: Isocitrate. OAA: Oxaloacetate. MDH Malate dehydrogenase. Succ: Succinate. ASP: Aspartate SCoA: Succinyl-CoA Fum: Fumarate. MAL: Malate. Other abbreviations are in the Text.