Intracellular signaling pathways control mitochondrial events associated with the development of ischemia-reperfusion-associated damage

Robert Sucher, Philipp Gehwolf, Thomas Kaier, Martin Hermann, Manuel Maglione, Rupert Oberhuber, Thomas Ratschiller, Andrey V. Kuznetsov, Florian Bösch, Andrey V. Kozlov, Muhammad Imtiaz Ashraf, Stefan Schneeberger, Gerald Brandacher, Robert Öllinger, Raimund Margreiter, Jakob Troppmair

Research output: Contribution to journalArticle

Abstract

Ischemia (I) and reperfusion (R) trigger a series of events, which culminate in severe injury to the transplanted organ. Cell death resulting from the formation of mitochondrial reactive oxygen species (ROS) coupled with the perturbation of mitochondrial Ca2+ homeostasis is central to the development of IR-associated tissue damage. We and others have shown recently that intracellular signaling pathways critically control these mitochondrial changes, making them potential targets for therapeutic intervention. Using a heterotopic murine heart transplant model as well as primary and immortalized cardiomyocyte cells we established the activity patterns of mitogen-activated protein kinases (MAPKs) ERK, JNK, and p38 during IR, and probed into their role in the perturbation of mitochondrial ROS and Ca2+ homeostasis, which are necessary for cardiomyocyte death. Our results showed a strong activation of all three MAPKs as well as a rise in mitochondrial ROS and Ca2+ during early reoxygenation. Inhibiting p38 kinase most efficiently prevented ROS production, Ca2+ overload and cell death, suggesting that targeting this signaling molecule may provide a possible strategy to limit the effects of IR.

Original languageEnglish (US)
Pages (from-to)922-930
Number of pages9
JournalTransplant International
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Keywords

  • Ca
  • Ischemia
  • Reactive oxygen species
  • Reperfusion
  • Signaling

ASJC Scopus subject areas

  • Transplantation

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  • Cite this

    Sucher, R., Gehwolf, P., Kaier, T., Hermann, M., Maglione, M., Oberhuber, R., Ratschiller, T., Kuznetsov, A. V., Bösch, F., Kozlov, A. V., Ashraf, M. I., Schneeberger, S., Brandacher, G., Öllinger, R., Margreiter, R., & Troppmair, J. (2009). Intracellular signaling pathways control mitochondrial events associated with the development of ischemia-reperfusion-associated damage. Transplant International, 22(9), 922-930. https://doi.org/10.1111/j.1432-2277.2009.00883.x