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Mitochondrial ATP-Sensitive K+ Channels Prevent Oxidative Stress, Permeability Transition and Cell Death

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Abstract

Ischemia followed by reperfusion results in impairment of cellular and mitochondrial functionality due to opening of mitochondrial permeability transition pores. On the other hand, activation of mitochondrial ATP-sensitive K+ channels (mitoKATP) protects the heart against ischemic damage. This study examined the effects of mitoKATP and mitochondrial permeability transition on isolated rat heart mitochondria and cardiac cells submitted to simulated ischemia and reperfusion (cyanide/aglycemia). Both mitoKATP opening, using diazoxide, and the prevention of mitochondrial permeability transition, using cyclosporin A, protected against cellular damage, without additive effects. MitoKATP opening in isolated rat heart mitochondria slightly decreased Ca2+ uptake and prevented mitochondrial reactive oxygen species production, most notably in the presence of added Ca2+. In ischemic cells, diazoxide decreased ROS generation during cyanide/aglycemia while cyclosporin A prevented oxidative stress only during simulated reperfusion. Collectively, these studies indicate that opening mitoKATP prevents cellular death under conditions of ischemia/reperfusion by decreasing mitochondrial reactive oxygen species release secondary to Ca2+ uptake, inhibiting mitochondrial permeability transition.

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Abbreviations

5-HD:

5-hydroxydecanoate

A.U.:

arbitrary units

CsA:

cyclosporin A

DZX:

diazoxide

H2DCF:

2′,7′-dichlorodihydro-fluorescein

H2DCFDA:

2′,7′-dichlorodihydrofluorescein diacetate

DCF:

2′,7′-dichlorofluorescein

mitoKATP:

mitochondrial ATP-sensitive K+ channels

MPT:

mitochondrial permeability transition

ROS:

reactive oxygen species

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil

    Heberty T. F. Facundo, Juliana G. de Paula & Alicia J. Kowaltowski

  2. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP, 05508-900, Brazil

    Alicia J. Kowaltowski

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  1. Heberty T. F. Facundo
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  2. Juliana G. de Paula
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  3. Alicia J. Kowaltowski
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Correspondence to Alicia J. Kowaltowski.

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Facundo, H.T.F., de Paula, J.G. & Kowaltowski, A.J. Mitochondrial ATP-Sensitive K+ Channels Prevent Oxidative Stress, Permeability Transition and Cell Death. J Bioenerg Biomembr 37, 75–82 (2005). https://doi.org/10.1007/s10863-005-4130-1

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  • DOI: https://doi.org/10.1007/s10863-005-4130-1

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