Changes in mitochondrial calcium concentration during the cardiac contraction cycle

Isenberg, Gerrit; Han, Song; Schiefer, Alfred; Wendt-Gallitelli, M F

doi:10.1093/cvr/27.10.1800

Cited by 87 publications

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“…These rapid transients indicate that mitochondrial metabolism can be regulated on a beat-to-beat basis by free Ca 2÷. Our results also confirm and extend a number of recent reports that mitochondrial free Ca 2+ may respond quickly to changes of cytosolic Ca 2+ after various stimuli [18,19,27,37,38]. To characterize such changes of mitochondrial free Ca 2+ with high temporal and spatial resolution, laser scanning confocal microscopy of Ca2+-indicating fluorophores is a useful and versatile tool.…”

Section: Resultssupporting

confidence: 87%

Mitochondrial free calcium transients during excitation‐contraction coupling in rabbit cardiac myocytes

et al. 1996

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Mitochondrlal free Ca 2+ may regulate mitochondrial ATP production during cardiac exercise. Here, using laser scanning confocal microscopy of adult rabbit cardiac myocytes co-loaded with Flue-3 to measure free Ca 2+ and tetramethylrhodamine methylester to identify mitochondria, we measured ! 2+ cytosolic and mitochondrla Ca transients during the contractile cycle. In resting cells, cytosolle and mitochondrlal Fiu,r~.3 signals were similar. During electrical pacing, transients of Flue-3 fluorescence occurred in both the cytosolic and mitochondrlal compartments. Both the mitochondrlal~ and the cytosollc transients were potentiated by isoproterenol. These experiments show directly that mitochondrlal free Ca 2+ rises and falls during excitation-contraction coupling in cardiac myocytes an6 that changes of mitochondrlal Ca z+ are kinetically competent to regulate mitochondrlal metabolism on a beat-to-beat basis.

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Section: Resultssupporting

confidence: 87%

Mitochondrial free calcium transients during excitation‐contraction coupling in rabbit cardiac myocytes

et al. 1996

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“…According to their calculations, total [Ca 2+ ] m rose from 0.5 to 1.3 mmol/kg dry weight within ∼45 ms, yielding a flux of ∼100 nmol/s/mg protein across the mCU. Thereafter, [Ca 2+ ] m decayed back to ∼1.3 mmol/kg dry weight within ∼400ms with a rate of ∼36 nmol/s/mg protein [100]. These values were ∼2 orders of magnitude greater than results from isolated mitochondria [76,77,79,129].…”

Section: Evidence For Fast Mitochondrial Ca 2+ Uptakementioning

confidence: 74%

“…Several studies indicate that by buffering [Ca 2+ ] c , rapid mitochondrial Ca 2+ uptake directly affects EC coupling [61,100,117,119,124,147,148,171]. When blocking mitochondrial Ca 2+ uptake, an increase of cytosolic Ca 2+ transients was observed ( Fig.…”

Section: Implications Of Rapid Mitochondrial Ca 2+ Uptake For Ec Coupmentioning

confidence: 95%

“…In the following years, a number of studies attempted to measure mitochondrial Ca 2+ uptake during EC coupling more directly, with quite controversial results [12,26,33,[59][60][61]68,[72][73][74]100,117,119,136,137,140,141,144,147,148,161,170,171,176,191,200,201,213] [26,117,119,148,176,191,200,201] or fluo-3 [33,144,170]) penetrate sarcolemmal and mitochondrial membranes and accumulate (to different degrees) in the mitochondrial matrix. To avoid contamination of the fluorescence signal by cytosolic Ca 2+ , the groups of Hansford, Silverman [59,60,74,136,137] and Bers [26,222] applied MnCl 2 in the extracellular solution.…”

Section: Evidence Against Fast Mitochondrial Ca 2+ Uptakementioning

confidence: 99%

“…The first experimental evidence for rapid mitochondrial Ca 2+ uptake in intact cardiac myocytes comes from the group of Wendt-Gallitelli and Isenberg [100,213]. By performing electronprobe microanalysis (EPMA) after shock freezing guinea-pig cardiac myocytes at different time points of a voltage-clamp-induced cytosolic Ca 2+ transient, they observed a mitochondrial Ca 2+ transient that peaked ∼15-20 ms after the cytosolic transient [213].…”

Section: Evidence For Fast Mitochondrial Ca 2+ Uptakementioning

confidence: 99%

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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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Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte

Winslow

Walker

Greenstein

2015

WIREs Mechanisms of Disease

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Calcium (Ca(2+)) plays many important regulatory roles in cardiac muscle cells. In the initial phase of the action potential, influx of Ca(2+) through sarcolemmal voltage-gated L-type Ca(2+) channels (LCCs) acts as a feed-forward signal that triggers a large release of Ca(2+) from the junctional sarcoplasmic reticulum (SR). This Ca(2+) drives heart muscle contraction and pumping of blood in a process known as excitation-contraction coupling (ECC). Triggered and released Ca(2+) also feed back to inactivate LCCs, attenuating the triggered Ca(2+) signal once release has been achieved. The process of ECC consumes large amounts of ATP. It is now clear that in a process known as excitation-energetics coupling, Ca(2+) signals exert beat-to-beat regulation of mitochondrial ATP production that closely couples energy production with demand. This occurs through transport of Ca(2+) into mitochondria, where it regulates enzymes of the tricarboxylic acid cycle. In excitation-signaling coupling, Ca(2+) activates a number of signaling pathways in a feed-forward manner. Through effects on their target proteins, these interconnected pathways regulate Ca(2+) signals in complex ways to control electrical excitability and contractility of heart muscle. In a process known as excitation-transcription coupling, Ca(2+) acting primarily through signal transduction pathways also regulates the process of gene transcription. Because of these diverse and complex roles, experimentally based mechanistic computational models are proving to be very useful for understanding Ca(2+) signaling in the cardiac myocyte.

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Changes in mitochondrial calcium concentration during the cardiac contraction cycle

Abstract: Mitochondrial calcium content changes during each individual contraction cycle; a substantial amount of calcium is taken up during the systole and released during later systole and diastole.

Cited by 87 publications

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Mitochondrial free calcium transients during excitation‐contraction coupling in rabbit cardiac myocytes

Mitochondrial free calcium transients during excitation‐contraction coupling in rabbit cardiac myocytes

Excitation-contraction coupling and mitochondrial energetics

Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte

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