Cardioprotection by Ischemic Preconditioning Preserves Mitochondrial Function and Functional Coupling Between Adenine Nucleotide Translocase and Creatine Kinase

Laclau, M.; Boudina, Sihem; Thambo, Jean Benoît; Tariosse, Liliane; Gouverneur, G.; Bonoron‐Adèle, Simone; Saks, Valdur; Garlid, Keith D.; Santos, Pierre Dos

doi:10.1006/jmcc.2001.1357

Cited by 101 publications

(51 citation statements)

References 34 publications

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“…Specifically, 18 O/ 31 P-NMR analysis of myocardial phosphotransfer dynamics demonstrated that in hearts with functional K ATP channels, IPC preserved total myocardial ATP turnover rate associated with concomitant preservation of rates of both ATP generation and hydrolysis as indicated from higher 18 O-labeling rates for ␥-ATP and P i . This is in line with previous reports that preconditioning preserves mitochondrial functions and the activities of cellular ATPases, thereby resulting in improved substrate oxidation, ionic homeostasis, and contractility (5,10,11,17,22). However, in hearts devoid of Kir6.2 and subjected to preconditioning episodes, total ATP turnover rate as well as 18 O labeling of ␥-ATP and P i remained comparable to nonpreconditioned hearts; this indicates failure to induce a stress-tolerant bioenergetic state, which is necessary for maintained metabolic homeostasis.…”

Section: Discussionsupporting

confidence: 92%

Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics

Gumina

Pucar

Bast

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

119

107

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Although ischemic preconditioning induces bioenergetic tolerance and thereby remodels energy metabolism that is crucial for postischemic recovery of the heart, the molecular components associated with preservation of cellular energy production, transfer, and utilization are not fully understood. Here myocardial bioenergetic dynamics were assessed by 18 O-assisted 31 P-NMR spectroscopy in control or preconditioned hearts from wild-type (WT) or Kir6. In contrast with WT hearts, preconditioning failed to preserve contractile recovery in Kir6.2-KO hearts, as tight coupling between postischemic performance and high-energy phosphoryl transfer was compromised in the KATP-channel-deficient myocardium. Thus intact KATP channels are integral in ischemic preconditioning-induced protection of cellular energetic dynamics and associated cardiac performance.ATP-sensitive K ϩ channel; cardioprotection; ischemia; metabolism ATP-SENSITIVE K ϩ (K ATP ) channels, which are highly expressed in myocardial sarcolemma, serve as membrane metabolic sensors that translate fluctuations in cellular energetics into regulation of electrical activity (1, 24,25,40). Nucleotide-dependent K ϩ permeation through Kir6.2, the inwardly rectifying pore-forming core of the K ATP channel, is gated by ATPase activity of the regulatory subunit SUR2A integrated with cellular metabolism through phosphotransfer networks (1, 2, 4, 13, 33, 42). This metabolic sensor function is underscored in response to ischemic challenge, where sarcolemmal K ATP channels have been proposed to respond to changes in cellular energetics that regulate ionic homeostasis (1,5,11,15, 24,25).In fact, Kir6.2-knockout (Kir6.2-KO) hearts, which lack functional K ATP channels, display a compromised ability to regulate electrical activity with loss of characteristic ST-segment elevation on the ECG during ischemia and poor contractile recovery (19,35). Furthermore, intact sarcolemmal K ATP channel function contributes to the reduction of infarct size afforded by ischemic preconditioning (IPC) (35), a cardioprotective phenomenon by which brief intermittent periods of ischemia protect the myocardium against a prolonged ischemic insult (21). Essential in the IPC-induced injury-tolerant state is the remodeling of energy transduction and cellular phosphotransfer networks, which results in maintained bioenergetic homeostasis and improved contractile recovery (10,22,26,29). Metabolic flux through creatine kinase, the major phosphotransfer enzyme in the myocardium and integrator of cellular metabolism with K ATP channels (1, 31), tightly correlates with cardioprotection of preconditioning (26). Although this correlation suggests a relationship between metabolic sensor activity and preservation of energetic homeostasis, it remains unexplored whether cardiac K ATP channels are required for IPC-mediated protection of cellular bioenergetics.Here, 18O-assisted 31 P-NMR spectroscopy captures bioenergetic dynamics in hearts from wild-type (WT) and Kir6.2-KO mice. Deletion of sarcolemmal K ATP channels ...

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Section: Discussionsupporting

confidence: 92%

Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics

Gumina

Pucar

Bast

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

119

107

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“…Besides, alteration in mito-CK flux might merely result from a change in kinetic factors. The concentration of substrates and products in the vicinity of mito-CK could indeed be altered by the decrease in translocase activity, by a change in the i.m.s. volume resulting from mitochondrial matrix contraction as recently observed in isolated mitochondria in the presence of CN (33), or by an alteration of the outer membrane permeability for adenine nucleotides as observed in models of ischemic reperfusion (34). Our data suggest that the control strength exerted by the mito-CK and by the ANT on the energy transfer depends on contractile activity.…”

Section: Discussionsupporting

confidence: 75%

31P NMR Detection of Subcellular Creatine Kinase Fluxes in the Perfused Rat Heart

Joubert¹,

Mazet

Matéo

et al. 2002

Journal of Biological Chemistry

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The subcellular fluxes of exchange of ATP and phosphocreatine (PCr) between mitochondria, cytosol, and ATPases were assessed by 31 P NMR spectroscopy to investigate the pathways of energy transfer in a steady state beating heart. Using a combined analysis of four protocols of inversion magnetization transfer associated with biochemical data, three different creatine kinase (CK) activities were resolved in the rat heart perfused in isovolumic control conditions: (i) a cytosolic CK functioning at equilibrium (forward, F f ‫؍‬ PCr 3 ATP, and reverse flux, F r ‫؍‬ ATP 3 PCr ‫؍‬ 3.3 mM⅐s ؊1 ), (ii) a CK localized in the vicinity of ATPases (MM-CK bound isoform) favoring ATP synthesis (F f ‫؍‬ 1.7 ؋ F r ), and (iii) a mitochondrial CK displaced toward PCr synthesis (F f ‫؍‬ 0.3 and F r ‫؍‬ 2.6 mM⅐s ؊1 ). This study thus provides the first experimental evidence that the energy is carried from mitochondria to ATPases by PCr (i.e. CK shuttle) in the whole heart. In contrast, a single CK functioning at equilibrium was sufficient to describe the data when ATP synthesis was partly inhibited by cyanide (0.15 mM). In this case, ATP was directly transferred from mitochondria to cytosol suggesting that cardiac activity modified energy transfer pathways. Bioenergetic implications of the localization and activity of enzymes within myocardial cells are discussed.Two major roles have been attributed to the creatine kinase (CK, 1 adenosine triphosphate creatine phosphotransferase, E.C. 2.7.3.2) reaction, which catalyzes the reversible exchange of high energy phosphate:Due to its equilibrium constant favoring ATP synthesis, CK acts as a spatial and temporal buffer for ATP. In addition, due to specific intracellular localization, CK has been suggested to play a key role in energy transfer from sites of ATP production to ATPases by a phosphocreatine (PCr)-creatine (Cr)-CK shuttle. In the myocardial cell, half of the total CK activity is present in the cytosol (cyto-CK), and the other half is accounted for by MM and mitochondrial (mito-CK) isoforms located in the vicinity of other enzymes: a particulate MM-bound CK located in close vicinity to the ATPases of myofibrils, sarcoplasmic reticulum (SR), and sarcolemma (SL) and a mito-CK isoform that is close to the adenine nucleotide translocase (ANT) in the intermembrane space (i.m.s.) of mitochondria. The vicinity of CK with other enzymes was shown to influence enzyme kinetics both in vitro (1, 2) and in skinned fiber preparations (3, 4). Mito-CK is the most obvious example of an exclusive localization in the restricted i.m.s. of the mitochondria where mito-CK octamers and their vicinity to ANT and porin have been proposed to efficiently channel energy from the mitochondria to cytosol (5, 6). The functional consequence of this localization was first evidenced in vitro where the activity of mito-CK changes the apparent affinity of respiration for externally added ADP in isolated mitochondria and saponin-skinned fibers (7-9). In other words there is a restriction of the outer mitochondrial m...

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“…Cross-sectional slices were stained with TTC after each treatment, scanned, and analyzed to report infarct size as the percentage of damaged tissue relative to the area at risk (IS % Area at Risk). Treatments deemed protective were found to exhibit a reduced infarct size to an extent similar to that reported elsewhere (85,114,140).…”

Section: Langendorff Perfused Heartssupporting

confidence: 82%

Mitochondrial Reactive Oxygen Species (ROS): Which ROS is Responsible for Cardioprotective Signaling?

Garlid

2000

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Cardioprotection by Ischemic Preconditioning Preserves Mitochondrial Function and Functional Coupling Between Adenine Nucleotide Translocase and Creatine Kinase

Cited by 101 publications

References 34 publications

Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics

Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics

31P NMR Detection of Subcellular Creatine Kinase Fluxes in the Perfused Rat Heart

Mitochondrial Reactive Oxygen Species (ROS): Which ROS is Responsible for Cardioprotective Signaling?

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