Na(+)-dependent Ca2+ efflux mechanism of heart mitochondria is not a passive Ca2+/2Na+ exchanger

Baysal, Kemal; Jung, Dennis W.; Gunter, Karlene K.; Gunter, Thomas E.; Brierley, Gerald P.

doi:10.1152/ajpcell.1994.266.3.c800

Cited by 75 publications

(54 citation statements)

References 23 publications

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“…Although blockade of the mitochondrial Na + /Ca 2+ exchangers appears consistent with the results obtained with CGP 37157, the possibility that the compound does not exclusively prevent the exit of Ca 2+ ions into the cytosol should not be ruled out. Baysal et al (1994) found that, in heart mitochondria, the Na + /Ca 2+ exchanger was electrogenic; therefore, if this also occurs in neuronal brain mitochondria, blockade of the exchanger may lead to changes in various mitochondrial functions.…”

Section: Discussionmentioning

confidence: 99%

Glycinergic nerve endings in hippocampus and spinal cord release glycine by different mechanisms in response to identical depolarizing stimuli

Luccini¹,

Romei²,

Raiteri³

2008

Journal of Neurochemistry

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Studies on hippocampal glycine release are extremely rare. We here investigated release from mouse hippocampus glycinergic terminals selectively pre‐labelled with [3H]glycine through transporters of the GLYT2 type. Purified synaptosomes were incubated with [3H]glycine in the presence of the GLYT1 blocker NFPS to abolish uptake (∼ 30%) through GLYT1. The non‐GLYT1‐mediated uptake was entirely sensitive to the GLYT2 blocker Org25543. Depolarization during superfusion with high‐K+ (15–50 mmol/L) provoked overflows totally dependent on external Ca2+, whereas in the spinal cord the 35 or 50 mmol/L KCl‐evoked overflow (higher than that in hippocampus) was only partly dependent on extraterminal Ca2+. In the hippocampus, the Ca2+‐dependent 4‐aminopyridine (1 mmol/L)‐evoked overflow was five‐fold lower than that in spinal cord. The component of the 10 μmol/L veratridine‐induced overflow dependent on external Ca2+ was higher in the hippocampus than that in spinal cord, although the total overflow in the hippocampus was only half of that in the spinal cord. Part of the veratridine‐evoked hippocampal overflow occurred by GLYT2 reversal and part by bafilomycin A1‐sensitive exocytosis dependent on cytosolic Ca2+ generated through the mitochondrial Na+/Ca2+ exchanger. As glycine sites on NMDA receptors are normally not saturated, understanding mechanisms of glycine release should facilitate pharmacological modulation of NMDA receptor function.

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Section: Discussionmentioning

confidence: 99%

Glycinergic nerve endings in hippocampus and spinal cord release glycine by different mechanisms in response to identical depolarizing stimuli

Luccini¹,

Romei²,

Raiteri³

2008

Journal of Neurochemistry

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“…The primary mitochondrial Ca 2+ efflux mechanism in cardiac cells is the mitochondrial Na + / Ca 2+ exchanger (mNCE) [54,77], which is presumably electrogenic [10,103] by exchanging 1 Ca 2+ for 3 Na + , with a K m for [Na + ] i of ∼8 mM [150]. Earlier studies, however, reported an electroneutral transport mode [48,49].…”

Section: Mitochondrial Ca 2+ Uptakementioning

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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“…The Na + -dependent mechanism, also known as mitochondrial Na + /Ca 2+ exchanger, is mainly found in heart and brain mitochondria and is an electrogenic process (52). In contrast, the Na + -independent efflux, is nonelectrogenic, and is present in liver and kidney mitochondria, and behaves as an active Ca 2+ /2H + exchanger (51).…”

Section: Ca 2+ As a Sensor In Cell Deathmentioning

confidence: 99%

Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling

Smaili

Hsu²,

Carvalho

et al. 2003

Braz J Med Biol Res

126

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Cellular Ca 2+ signals are crucial in the control of most physiological processes, cell injury and programmed cell death through the regulation of a number of Ca 2+ -dependent enzymes such as phospholipases, proteases, and nucleases. Mitochondria along with the endoplasmic reticulum play pivotal roles in regulating intracellular Ca 2+ content. Mitochondria are endowed with multiple Ca 2+ transport mechanisms by which they take up and release Ca 2+ across their inner membrane. During cellular Ca 2+ overload, mitochondria take up cytosolic Ca 2+ , which in turn induces opening of permeability transition pores and disrupts the mitochondrial membrane potential (Dy m ). The collapse of Dy m along with the release of cytochrome c from mitochondria is followed by the activation of caspases, nuclear fragmentation and cell death. Members of the Bcl-2 family are a group of proteins that play important roles in apoptosis regulation. Members of this family appear to differentially regulate intracellular Ca 2+ level. Translocation of Bax, an apoptotic signaling protein, from the cytosol to the mitochondrial membrane is another step in this apoptosis signaling pathway. Correspondence

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Na(+)-dependent Ca2+ efflux mechanism of heart mitochondria is not a passive Ca2+/2Na+ exchanger

Cited by 75 publications

References 23 publications

Glycinergic nerve endings in hippocampus and spinal cord release glycine by different mechanisms in response to identical depolarizing stimuli

Glycinergic nerve endings in hippocampus and spinal cord release glycine by different mechanisms in response to identical depolarizing stimuli

Excitation-contraction coupling and mitochondrial energetics

Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling

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