Opening mitochondrial KATP in the heart – what happens, and what does not happen

Abstract There is considerable evidence that opening the mitochondrial ATP-sensitive potassium channel (mitoKATP) is cardioprotective in ischemia-reperfusion. Two prominent questions surround the role of mitoKATP in the cardiomyocyte: How does opening mitoKATP protect? What is the normal physiological role of mitoKATP in the heart? Before these questions can be addressed, it is necessary to agree on the bioenergetic consequences of opening mitoKATP, and this distills down to a single question – does opening mitoKATP cause significant uncoupling or not? The evidence strongly indicates that it does not and that reports of uncoupling and inhibition of Ca2+ uptake are the result of using toxic concentrations of KATP channel openers. Thus, opening mitoKATP results in increased K+ flux that is sufficient to change mitochondrial volume but is insufficient to cause significant depolarization of membrane potential. The volume changes, however, have significant bioenergetic consequences for energy coupling in the cell.

[1]  R. Jennings,et al.  Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. , 1986, Circulation.

[2]  E. Marbán,et al.  Nicorandil , 2024, Reactions Weekly.

[3]  R. Portenhauser,et al.  Inhibition of mitochondrial metabolism by the diabetogenic thiadiazine diazoxide. I. Action on succinate dehydrogenase and TCA-cycle oxidations. , 1971, Biochemical pharmacology.

[4]  A. Halestrap.  The regulation of the oxidation of fatty acids and other substrates in rat heart mitochondria by changes in the matrix volume induced by osmotic strength, valinomycin and Ca2+. , 1987, The Biochemical journal.

[5]  N. Di Fonzo,et al.  The Existence of the K+ Channel in Plant Mitochondria* , 1999, The Journal of Biological Chemistry.

[6]  A. Terzic,et al.  Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function. , 1998, American journal of physiology. Heart and circulatory physiology.

[7]  R. Portenhauser,et al.  Inhibition of mitochondrial metabolism by the diabetogenic thiadiazine diazoxide. II. Interaction with energy conservation and ion transport. , 1971, Biochemical pharmacology.

[8]  D. Nicholls,et al.  Mitochondria from Hamster Brown‐Adipose Tissue , 1972 .

[9]  S. K. Ratkje,et al.  On the nature of ion leaks in energy-transducing membranes. , 1989, Biochimica et biophysica acta.

[10]  D. Diresta,et al.  Kinetics of inhibition and binding of dicyclohexylcarbodiimide to the 82,000-dalton mitochondrial K+/H+ antiporter. , 1986, The Journal of biological chemistry.

[11]  E. Marbán,et al.  Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. , 1998, Circulation research.

[12]  G. Grover,et al.  ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. , 2000, Journal of molecular and cellular cardiology.

[13]  K. Garlid.  Cation transport in mitochondria--the potassium cycle. , 1996, Biochimica et biophysica acta.

[14]  A. Szewczyk,et al.  Potassium channel opener, RP 66471, induces membrane depolarization of rat liver mitochondria. , 1995, Biochemical and biophysical research communications.

[15]  A. Terzic,et al.  ATP‐sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria , 1999, The Journal of physiology.

[16]  E. P. Kennedy,et al.  The requirements of the fatty acid oxidase complex of rat liver. , 1948, The Journal of biological chemistry.

[17]  V. Saks,et al.  Early alteration of the control of mitochondrial function in myocardial ischemia. , 1997, Journal of molecular and cellular cardiology.

[18]  Demonstration of glibenclamide-sensitive K+ fluxes in rat liver mitochondria. , 1993, Biochemistry and molecular biology international.

[19]  G. Grover,et al.  Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. , 1995, Circulation research.

[20]  K D Garlid,et al.  On the mechanism of regulation of the mitochondrial K+/H+ exchanger. , 1980, The Journal of biological chemistry.

[21]  J. Newburger,et al.  Cardioprotective effects of the potassium channel opener cromakalim: stereoselectivity and effects on myocardial adenine nucleotides. , 1991, The Journal of pharmacology and experimental therapeutics.

[22]  Yongge Liu,et al.  Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? , 1998, Circulation.

[23]  A. Halestrap.  The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. , 1989, Biochimica et biophysica acta.

[24]  P. Diolez,et al.  Quantitative studies of enzyme-substrate compartmentation, functional coupling and metabolic channelling in muscle cells. , 1998 .

[25]  P. Mitchell.  CHEMIOSMOTIC COUPLING IN OXIDATIVE AND PHOTOSYNTHETIC PHOSPHORYLATION , 1966, Biological reviews of the Cambridge Philosophical Society.

[26]  M. Smith,et al.  Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. , 1997, Circulation research.

[27]  N. Chandel,et al.  Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Vanden Hoek,et al.  Reactive Oxygen Species Released from Mitochondria during Brief Hypoxia Induce Preconditioning in Cardiomyocytes* , 1998, The Journal of Biological Chemistry.

[29]  J. Shapiro,et al.  Intracellular Reactive Oxygen Species Mediate the Linkage of Na+/K+-ATPase to Hypertrophy and Its Marker Genes in Cardiac Myocytes* , 1999, The Journal of Biological Chemistry.

[30]  EduardoMarbán,et al.  Modulation of Mitochondrial ATP-Dependent K+ Channels by Protein Kinase C , 1998 .

[31]  V. Yarov-Yarovoy,et al.  The Mitochondrial K Channel as a Receptor for Potassium Channel Openers (*) , 1996, The Journal of Biological Chemistry.