Cardiac Energy Metabolism Homeostasis: Role of Cytosolic Calcium

Abstract 

R. S. Balaban. Cardiac Energy Metabolism Homeotasis: Role of Cytosolic Calcium. Journal of Molecular and Cellular Cardiology (2002) 34, 1259–1271. The heart is capable of dramatically altering its overall energy flux with minimal changes in the concentrations of metabolites that are associated with energy metabolism. This cardiac energy metabolism homeostasis is discussed with regard to the potential cytosolic control network responsible for controlling the major energy conversion pathway, oxidative phosphorylation in mitochondria. Several models for this cytosolic control network have been proposed, but a cytosolic Ca²⁺ dependent parallel activation scheme for metabolism and work is consistent with most of the experimental results. That model proposes that cytosolic Ca²⁺ regulates both the utilization of ATP by the work producing ATPases as well as the mitochondrial production of ATP. Recent studies have provided evidence supporting this role of cytosolic Ca²⁺. These data include the demonstration that mitochondrial [Ca²⁺] can track cytosolic [Ca²⁺] and that the compartmentation of cytosolic [Ca²⁺] can facilitate this process. On the metabolic side, Ca²⁺ has been shown to rapidly activate several steps in oxidative phosphorylation, including F₁F₀-ATPase ATP production as well as several dehydrogenases, which results in a homeostasis of mitochondrial metabolites similar to that observed in the cytosol. Numerous problems with the Ca²⁺ parallel activation hypothesis remain including the lack of specific mechanisms of mitochondrial Ca²⁺ transport and regulation of F₁F₀-ATPase, the time dependence of Ca²⁺ activation of cytosolic ATPases as well as oxidative phosphorylation, and the role of cytosolic compartmentation. In addition, the lack of cytosolic or mitochondrial [Ca²⁺] measurements under in vivo conditions is problematic. Several lines of investigation to address these issues are suggested. A model of the cardiac energy metabolism control network is proposed that includes a Ca²⁺ parallel activation component together with more classical elements including metabolite feedback and cytosolic compartmentation.

Keywords: Mitochondria, Adenosine triphosphate, Adenosine diphosphate, Proton-motive force, Sarcoplasmic reticulum, Respiration

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• f1 Please address all correspondence to: Robert S. Balaban, Laboratory of Cardiac Energetics National Heart Lung and Blood Institute, Building 10, Room B1 D161, Bethesda, MD 20892-0001, USA. Tel: 301-496-3658; Fax: 301-402-2389; E-mail:rsb@zeus.nhlbi.nih.gov