Ca2+ As a Second Messenger within Mitochondria of the Heart and other Tissues

Denton, Richard M.; McCormack, James G.

doi:10.1146/annurev.ph.52.030190.002315

Cited by 285 publications

(165 citation statements)

References 44 publications

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“…An electroneutral transport mode was also reported in the earliest studies identifying mNCE [3,56]. An increase in mitochondrial Ca 2+ concentration plays a major role in the stimulation of mitochondrial ATP production in response to a change in cardiac work, both by stimulation of Ca 2+ -sensitive dehydrogenases [57] and by activation of other sites in the respiratory chain [58].…”

Section: Mitochondrial Na-ca Exchangementioning

confidence: 76%

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

O’Rourke

Maack

2007

Drug Discovery Today: Disease Models

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Ca 2+ is well known as the central player in cardiac cell physiology, mediating Ca 2+ activation of myosin ATPase and contraction, the stimulation of Ca 2+ -activated signaling pathways and modulation of mitochondrial energy production. Abnormalities of Ca 2+ handling are a well-studied mechanism of decompensation in heart failure. Less appreciated is the role of cytosolic Na + (Na i + ), which can dramatically influence the transfer rates and distribution of Ca 2+ among the intracellular compartments of the myocyte. Since Na i + can vary widely under different physiological and pathological conditions, and its effects depend on multiple ion gradients and membrane electrical potentials, unraveling the global influence of Na i + on cell function is complex, requiring an integrative view of cardiomyocyte physiology. Here, we discuss how abnormal Na i + regulation not only influences the cytosolic Ca 2+ transient and the cellular action potential but also alters mitochondrial Ca 2+ uptake and the balance of energy supply and demand of the cardiomyocyte, which may contribute to oxidative stress and cardiac decompensation. The implications for sudden cardiac death and the potential for novel therapeutic interventions are discussed. Na i + balance: the playersNa i + balance in the heart cell is maintained by a variety of ion channels, pumps and exchangers whose function is strongly influenced by the transmembrane gradients of various ions, and in some cases, by the electrical potential across the sarcolemmal or organelle membranes ( Fig. 1; see [1] for a review). At the sarcolemma, two well-known processes contribute to unidirectional Na + fluxes during the cardiac cycle; voltage-dependent Na + channels mediate the rapid inward Na + current (I Na ) during the upstroke of the cellular action potential and may also contribute to persistent Na + influx, while the Na + /K + ATPase (NKA) utilizes the energy released by ATP hydrolysis to pump Na + out of the cell against a concentration gradient in exchange for K + in an electrogenic process (3Na + :2K + ). A variety of electroneutral exchangers also influence Na i + when ion homeostasis is disturbed under pathological conditions; these include the Na + /H + exchanger (NHE), the Na + /HCO 3 -cotransporter (NBC), the Na + /K + / 2Cl -cotransporter (NKCC) and the Na + /Mg 2+ exchanger (NMgX). Influx of Na + through these pathways is generally well compensated by NKA action. Uniquely, under physiological conditions, the sarcolemmal Na + /Ca 2+ exchanger (NCX) operates in both the forward-mode (Ca 2+ extrusion/Na + entry) and reverse-mode (Ca 2+ entry/Na + extrusion) during different phases of the cardiac cycle, depending on the dynamically changing membrane potential and gradients of Na + and Ca 2+ across the sarcolemma. Its sensitivity to membrane voltage is

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Section: Mitochondrial Na-ca Exchangementioning

confidence: 76%

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

O’Rourke

Maack

2007

Drug Discovery Today: Disease Models

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“…The classical respiratory controlhypothesis of Chance and Williams [37] implies that the rate of respiration is regulated by the availability of ADP to the F 1 /F 0 -ATPase. This is based on the observation that when adding ADP to a suspension of isolated mitochondria, O 2 consumption increases ("state 3 respiration"), and when ADP and/or P i in the assay are consumed, the rate of respiration decreases again ("state 4 respiration" [53,54,56,57,127,128] (Fig. 3A and B), it was proposed that Ca 2+ rather than ADP may regulate respiration in vivo [106].…”

Section: Energy Supply and Demand Matchingmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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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...

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“…There appear to be many factors contributing to the control of the TCA cycle and oxidative phosphorylation in mitochondria, not all of which are clearly understood (reviewed [7,[36][37][38]). ICDH is an important control point [9,11,36].…”

Section: A Ap-driven Substrate Cycle Between Ic and Kg Mediated By Trmentioning

confidence: 99%

“…Substrate cycling between IC and KG might therefore provide a mechanism which would allow flux through the TCA cycle to follow precisely the changes in energy demand and thus match immediately the changes in energy consumption and production. It is now well established that Ca2' is an important activator of the dehydrogenases of the TCA cycle, including NAD-ICDH [7,38]. The concentration of Ca2+ in the cytoplasm and hence in the mitochondrial matrix is regulated by hormones and other messengers.…”

Section: A Ap-driven Substrate Cycle Between Ic and Kg Mediated By Trmentioning

confidence: 99%

“…The presence of high external Mg2+ concentrations was intended to minimize this effect [8] but the Mg2+ permeability of the inner mitochondrial membrane is rather low [38]. That the NADP-ICDH in vivo should operate in re-verse is a critical prediction of our hypothesis and further experimental work in this area would be valuable.…”

Section: Evidence For Reversibility Of Icdh In Isolated Mitochondriamentioning

confidence: 99%

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Proton‐translocating transhydrogenase and NAD‐ and NADP‐linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria

1994

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H'-transhydrogenase (H'-Thase) and NADP-linked isocitrate dehydrogenase (NADP-ICDH) are very active in animal mitochondria but their physiological function is only poorly understood. This is especially so in the case of the heart and muscle, where there are no major consumers of NADPH. We propose here that H'-Thase and NADP-ICDH have a combined function in the fine regulation of the activity of the tricarboxylic acid (TCA) cycle, providing enhanced sensitivy to changes in energy demand. This is achieved through cycling of substrates by NAD-linked ICDH, NADP-linked ICDH and H'-Thase. It is proposed that NAD-ICDH operates in the forward direction of the TCA cycle, but NADP-ICDH is driven in reverse by elevated levels of NADPH resulting from the action of the transmembrane proton electrochemical potential gradient (dp) on H'-Thase. This has the effect of increasing the sensitivity to allosteric modifiers of NAD-ICDH (NADH, ADP, ATP, Ca" etc), potentially giving rise to large changes in the net flux from iso-citrate to a-ketoglutarate. Furthermore, changes in the level of Ap resulting from changes in the demand for ATP would, via H'-Thase, shift the redox state of the NADP pool and this, in turn, would lead to a change in the rate of the reaction catalysed by NADP-ICDH and hence to an additional and complementary effect on the net metabolic flux from isocitrate to a-ketoglutarate.Other consequences of this substrate cycle are, (i) the production of heat at the expense of Ap, which may contribute to thermoregulation in the animal, and (ii) an increased rate of dissipation of Ap (leak).

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Ca2+ As a Second Messenger within Mitochondria of the Heart and other Tissues

Cited by 285 publications

References 44 publications

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

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

Excitation-contraction coupling and mitochondrial energetics

Proton‐translocating transhydrogenase and NAD‐ and NADP‐linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria

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