Intracellular Free Calcium and Mitochondrial Membrane Potential in Ischemia/Reperfusion and Preconditioning

Ylitalo, Kari; Ala-Rämi, Antti; Liimatta, Erkki; Peuhkurinen, Keijo; Hassinen, Ilmo E.

doi:10.1006/jmcc.2000.1157

Cited by 76 publications

(46 citation statements)

References 38 publications

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“…These findings support a plausible mechanism by which mitoK ATP channel opening during ischemia 1) reduces the rate of ATP loss (22,37,40), 2) reduces the rate of adenine nucleotide degradation so that ADP is available for phosphorylation upon reperfusion (26), and 3) reduces ⌬⌿ and Ca 2ϩ accumulation (63,67). These effects preserve mitochondria so that, upon reperfusion, they can return to their normal function of providing adequate ATP supply to cytosolic ATPases.…”

Section: Discussionmentioning

confidence: 52%

“…Protected hearts exhibit a reduced rate of ATP loss during ischemia (22,37,40). Mitochondrial ⌬⌿ is lower during ischemia, leading to reduced Ca 2ϩ accumulation (63,67), which has been identified as being important for cardioprotection (25,36). Jennings et al (26) have shown that adenine nucleotides are rapidly degraded during ischemia and that IPC retards the rate of degradation.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Santos

Kowaltowski

Laclau

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

203

141

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. Mechanisms by which opening the mitochondrial ATP-sensitive K ϩ channel protects the ischemic heart. Am J Physiol Heart Circ Physiol 283: H284-H295, 2002. First published February 14, 2002 10.1152/ajpheart. 00034.2002-Diazoxide opening of the mitochondrial ATPsensitive K ϩ (mitoKATP) channel protects the heart against ischemia-reperfusion injury by unknown mechanisms. We investigated the mechanisms by which mitoKATP channel opening may act as an end effector of cardioprotection in the perfused rat heart model, in permeabilized fibers, and in rat heart mitochondria. We show that diazoxide pretreatment preserves the normal low outer membrane permeability to nucleotides and cytochrome c and that these beneficial effects are abolished by the mitoKATP channel inhibitor 5-hydroxydecanoate. We hypothesize that an open mitoK ATP channel during ischemia maintains the tight structure of the intermembrane space that is required to preserve the normal low outer membrane permeability to ADP and ATP. This hypothesis is supported by findings in mitochondria showing that small decreases in intermembrane space volume, induced by either osmotic swelling or diazoxide, increased the half-saturation constant for ADP stimulation of respiration and sharply reduced ATP hydrolysis. These effects are proposed to lead to preservation of adenine nucleotides during ischemia and efficient energy transfer upon reperfusion. mitochondria; metabolism; creatine kinase; membrane transport; cytochrome c; ischemic preconditioning THERE IS NOW GENERAL AGREEMENT that the mitochondrial ATP-sensitive K ϩ (mitoK ATP ) channel plays a pivotal role in cardioprotection against ischemia-reperfusion injury (16,17,20,21,36,64); however, little is known about the mechanism of this protection. It has been proposed that mitoK ATP channel opening triggers protection by increasing the generation of reactive oxygen species (ROS) (13, 47), and this effect has now been demonstrated by several laboratories (10,13,44,57). We proposed that the mitoK ATP channel is also an end effector of protection (16), and many studies have confirmed that the mitoK ATP channel is required to be open during the ischemic phase (11,46,58,59,64). Thus the mitoK ATP channel is both a trigger and an end effector of cardioprotection, and these two roles are temporally and mechanistically distinct.We have previously suggested that cardioprotection by mitoK ATP channel opening is due in part to volume regulation, which serves to preserve the structurefunction of the intermembrane space (IMS) and the low permeability of the outer membrane to nucleotides (31). Nucleotide transport across the outer membrane occurs primarily through the voltage-dependent anion channel (VDAC) (2, 34, 49, 50). We hypothesize that VDAC permeability to nucleotides is regulated in part by IMS volume, which in turn is regulated by K ϩ flux across the inner membrane.This study focuses on the end effector mechanisms by which an open mitoK ATP channel protects the heart during ischemia and reperfusion. We show, in sapon...

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Santos

Kowaltowski

Laclau

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

203

141

View full text Add to dashboard Cite

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“…However, it should be noted that the extent of ΔΨ m loss during metabolic inhibition was not examined in this study and it has been argued that diazoxide will induced a marked depolarization under ischemic conditions [67]. Moreover, IPC has been shown to enhance mitochondrial membrane depolarization during ischemia [68], which may contribute to the protective effect.…”

Section: Possible Independence Of Protection and Depolarization Of δψ Mmentioning

confidence: 86%

Mitochondrial K channels in cell survival and death

Ardehali¹,

O’Rourke²

2005

Journal of Molecular and Cellular Cardiology

196

151

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Since the discovery of the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) more than 13 years ago, it has been implicated in the processes of ischemic preconditioning (IPC), apoptosis and mitochondrial matrix swelling. Different approaches have been employed to characterize the pharmacological profile of the channel, and these studies strongly suggest that cellular protection well correlates with the opening of mitoK ATP . However, there are many questions regarding mitoK ATP that remain to be answered. These include the very existence of mitoK ATP itself, its degree of importance in the process of IPC, its response to different pharmacological agents, and how its activation leads to the process of IPC and protection against cell death. Recent findings suggest that mitoK ATP may be a complex of multiple mitochondrial proteins, including some which have been suggested to be components of the mitochondrial permeability transition pore. However, the identity of the pore-forming unit of the channel and the details of the interactions between these proteins remain unclear. In this review, we attempt to highlight the recent advances in the physiological role of mitoK ATP and discuss the controversies and unanswered questions.

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“…Preconditioning, a series of brief periods of ischemia and reperfusion, protects the myocardium from deleterious events associated with extended durations of ischemia and reperfusion (7)(8)(9). Cardioprotection afforded by preconditioning appears mediated, in part, by the production of oxygen radicals (35)(36)(37)(38)(39)(40) and is associated with reductions in Ca 2ϩ overload (7,(41)(42)(43) and free radical production (44) during extended periods of ischemia͞ reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion

Bulteau

Lundberg

Ikeda‐Saito

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

129

118

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Prooxidents can induce reversible inhibition or irreversible inactivation and degradation of the mitochondrial enzyme aconitase. Cardiac ischemia͞reperfusion is associated with an increase in mitochondrial free radical production. In the current study, the effects of reperfusion-induced production of prooxidants on mitochondrial aconitase and proteolytic activity were determined to assess whether alterations represented a regulated response to changes in redox status or oxidative damage. Evidence is provided that ATP-dependent proteolytic activity increased during early reperfusion followed by a time-dependent reduction in activity to control levels. These alterations in proteolytic activity paralleled an increase and subsequent decrease in the level of oxidatively modified protein. In vitro data supports a role for prooxidants in the activation of ATP-dependent proteolytic activity. Despite inhibition during early periods of reperfusion, aconitase was not degraded under the conditions of these experiments. Aconitase activity exhibited a decline in activity followed by reactivation during cardiac reperfusion. Loss and regain in activity involved reversible sulfhydryl modification. Aconitase was found to associate with the iron binding protein frataxin exclusively during reperfusion. In vitro, frataxin has been shown to protect aconitase from [4Fe-4S] 2؉ cluster disassembly, irreversible inactivation, and, potentially, degradation. Thus, the response of mitochondrial aconitase and ATP-dependent proteolytic activity to reperfusioninduced prooxidant production appears to be a regulated event that would be expected to reduce irreparable damage to the mitochondria.H ighly reactive oxygen derived free radicals, such as superoxide anion (O 2•Ϫ ) and the prooxidant hydrogen peroxide (H 2 O 2 ), can interact with a variety of cellular components, altering both structure and function (1). Although evidence for these reactions has long been sought as indication of free radical involvement in degenerative disorders, recent evidence indicates that these processes also participate in the regulation of cellular function (1, 2). This finding is exemplified by the discovery of enzymatic systems, such as thioredoxin reductase͞thioredoxin (3), glutaredoxin (4), methione sulfoxide reductase (5), and sulfiredoxin (6), which catalyze reversal of oxidative modifications to protein and restoration of protein function. Additionally, receptor-and enzyme-mediated systems exist that catalyze the production of free radicals in response to changes in extracellular and intracellular factors (1, 2). It is therefore important that free radicals produced during physiological and pathophysiological conditions be investigated not simply for their potential to carry out damaging processes but also to induce appropriate alterations in response to changes in cellular homeostasis.Reduction and͞or cessation of blood f low to myocardial tissue, termed ischemia, occurs primarily as a result of formation of atherosclerotic lesions in the coronary arteries...

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Intracellular Free Calcium and Mitochondrial Membrane Potential in Ischemia/Reperfusion and Preconditioning

Cited by 76 publications

References 38 publications

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Mitochondrial K channels in cell survival and death

Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion

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Intracellular Free Calcium and Mitochondrial Membrane Potential in Ischemia/Reperfusion and Preconditioning

Cited by 76 publications

References 38 publications

Mechanisms by which opening the mitochondrial ATP- sensitive K+channel protects the ischemic heart

Mechanisms by which opening the mitochondrial ATP- sensitive K+channel protects the ischemic heart

Mitochondrial K channels in cell survival and death

Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion

Contact Info

Product

Resources

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Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart