To search for the stimuli involved in activating the mitogen-activated protein kinases (MAPKs) during ischaemia and reperfusion, we simulated the event in a system in vitro conducive to continuous and non-invasive measurements of several major perturbations that occur at the time: O2 tension, mitochondrial respiration and energy status. Using H9c2 cells (a clonal line derived from rat heart), we found that activation of the extracellular signal-regulated MAPKs (ERKs) on reoxygenation was abolished if the mitochondria were inhibited prior to and during reoxygenation. Re-introduction of O2per se is therefore not sufficient to activate the ERKs. Recovery and maintenance of cellular ATP levels by mitochondrial respiration is necessary, although ATP recovery alone is not sufficient. ERK activation by H2O2, but not phorbol esters, was also sensitive to mitochondrial inhibition. Thus, reoxygenation and H2O2-mediated oxidative stress share a mechanism of ERK activation that is ATP- or mitochondrion-dependent, and this common feature suggests that the reoxygenation response is mediated by reactive oxygen species. A correlation between ERK activity and ATP levels was also found during the anoxic phase of ischaemia, an effect that was not due to substrate limitation for the kinases. Our results reveal the importance of cellular metabolism in ERK activation, and introduce ATP as a novel participant in the mechanisms underlying the ERK cascade.
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Research Article|
June 26 2000
Mitochondrial ATP production is necessary for activation of the extracellular-signal-regulated kinases during ischaemia/reperfusion in rat myocyte-derived H9c2 cells
Lindy ABAS;
Lindy ABAS
1
1To whom correspondence should be addressed (e-mail mabas@;cyllene.uwa.edu.au).
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Marie A. BOGOYEVITCH;
Marie A. BOGOYEVITCH
1Department of Biochemistry, University of Western Australia, Nedlands, W.A. 6907, Australia
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Michael GUPPY
Michael GUPPY
1Department of Biochemistry, University of Western Australia, Nedlands, W.A. 6907, Australia
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Publisher: Portland Press Ltd
Received:
January 04 2000
Revision Received:
March 23 2000
Accepted:
April 27 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 349 (1): 119–126.
Article history
Received:
January 04 2000
Revision Received:
March 23 2000
Accepted:
April 27 2000
Citation
Lindy ABAS, Marie A. BOGOYEVITCH, Michael GUPPY; Mitochondrial ATP production is necessary for activation of the extracellular-signal-regulated kinases during ischaemia/reperfusion in rat myocyte-derived H9c2 cells. Biochem J 1 July 2000; 349 (1): 119–126. doi: https://doi.org/10.1042/bj3490119
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