Excitation-contraction coupling and mitochondrial energetics

Abstract

Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

Physical Coupling Supports the Local Ca2+ Transfer between Sarcoplasmic Reticulum Subdomains and the Mitochondria in Heart Muscle

“…However, it has been discussed more and more that the SR-mitochondrial Ca 2ϩ transfer is a significant regulatory factor of excitation-contraction and excitation-oxidative metabolic coupling (recently reviewed in Refs. [42][43][44]. This direction is strengthened by our results that caffeine stimulation of RyR2-mediated Ca 2ϩ release also evoked a rapid increase in the NAD(P)H levels in the pRHM mitochondria, underlying the metabolic relevance of the SR-mitochondrial complexes.…”

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

“…These observations suggest that CK-M overexpression does not alter fundamental contractile function or maximal calcium release in the isolated myocyte, whose energetic demands while unloaded and stimulated at 0.5 Hz are more than an order of magnitude below that of the in vivo, hemodynamically loaded mouse heart beating at 10 Hz. This was an important avenue for investigation, because the products of ATP hydrolysis (e.g., ADP + inorganic phossphate [Pi]) inhibit calcium pump activity and adversely affect the relationship between calcium and the myofilaments (37,38). Indeed, the reduction in PCr in TAC hearts could be associated with an increase in Pi that cannot be quantified in vivo.…”

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

“…Taking all of these ideas into consideration, we have proposed a novel mechanism that may contribute to functional decompensation and/or sudden death in the context of chronic metabolic stress, such as during postischemic remodeling, hypertrophy and heart failure [68]. Na i + loading in the diseased heart may partially compensate for impaired contractility by enhancing SR Ca 2+ load; however, the effect of elevated Na i + on mitochondrial Ca 2+ loading induces a mismatch between NADH supply and energy demand.…”