Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia.

Miyata, Haruo; Lakatta, Edward G.; Stern, Michael D.; Silverman, Howard S.

doi:10.1161/01.res.71.3.605

Cited by 172 publications

(107 citation statements)

References 32 publications

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“…This decrease is known to be related to the oxidative stress (Chen et al 2007). Indeed, at the beginning of reperfusion, calcium invades the mitochondrial matrix (Miyata et al 1992) and opens the permeability transition pore, leading to release of NADH from the mitochondrial matrix (Batandier et al 2004). Furthermore, it activates the α-ketoglutarate dehydrogenase, which triggers succinate accumulation in the mitochondrial environment (Sentex et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Mourmoura

Leguen

Dubouchaud

et al. 2010

AGE

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Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10-or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H 2 O 2 release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H 2 O 2 when they oxidize FADH 2 -linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration AGE (2011) of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.

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Section: Discussionmentioning

confidence: 99%

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Mourmoura

Leguen

Dubouchaud

et al. 2010

AGE

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“…In all studies using the Mn 2+ -quench method [59,60,74,136,137], no beat-to-beat oscillations of [Ca 2+ ] m in response to cytosolic Ca 2+ -transients could be detected ( Fig. 5A and B).…”

Section: Evidence Against Fast Mitochondrial Ca 2+ Uptakementioning

confidence: 91%

“…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%

“…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. Mn 2+ enters the cell, presumably via L-type Ca 2+ -channels, binds to cytosolic indo-1 with ∼20-fold higher affinity than Ca 2+ and quenches its fluorescence [123,137,222].…”

Section: Evidence Against 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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“…In the reperfused myocardium, excess calcium invades the mitochondria [35] and triggers noticeable ROS production [36]. ROS inhibit the aconitase enzyme within the Krebs cycle [37], which blocks ATP synthesis and triggers the functional abnormalities that characterize reperfusion [38].…”

Section: Introductionmentioning

confidence: 99%

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

Evangelia¹,

Couturier²,

Dubouchaud³

2015

J Diabetes Metab

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Compared to the lean Lou/C rat, the Wistar rat develops increased body weight and abdominal adiposity (IAA). The aim of this study was to compare the functional response to cardiac ischemia/reperfusion of 3-month old Wistar rats with age-matched Lou/C rats, and to explain the differences with regards to mitochondrial hydrogen-peroxide release (mH 2 O 2 r). Langendorff-perfused hearts of Lou/C and Wistar rats were subjected to ischemia (25 min) followed by reperfusion (30 min). Cardiac function was monitored throughout the experiment. Mitochondria were extracted before and after ischemia, and their oxidative capacities, mH 2 O 2 r, and activity of the respiratory-chain complex were measured. The IAA of Wistar rats was associated with slight glucose intolerance and noticeable functional abnormalities of the myocardium during post-ischemic reperfusion. Cardio-toxicity was related to maintenance of the activity of respiratory-chain complex II and increased mH 2 O 2 r, whereas cardio-protection in lean Lou/C rats occurred through reduced complex-II activity and mH 2 O 2 r. In conclusion, IAA and/or systemic glucose intolerance maintained complex-II activity during post-ischemic reperfusion, thus increasing mH 2 O 2 r through reverse electron flux and inducing significantly increased cardio-toxicity. Inhibitors of respiratory complex II could thus help protect the heart against ischemia/reperfusion in obese individuals.

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Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia.

Abstract: Mitochondrial calcium overload has been suggested as a marker for irreversible injury in the ischemic heart. A new technique is used to measure dynamic changes in mitochondrial free calcium concentration ([Ca2+]

Cited by 172 publications

References 32 publications

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Excitation-contraction coupling and mitochondrial energetics

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

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