Glycogen synthase kinase-3β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore

Magdalena Juhaszova, Dmitry B. Zorov, Suhn Hee Kim, Salvatore Pepe, Qin Fu, Kenneth W. Fishbein, Bruce D. Ziman, Su Wang, Kirsti Ytrehus, Christopher L. Antos, Eric N. Olson, Steven J. Sollott

Research output: Contribution to journalArticle

Abstract

Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3β (GSK-3β). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3β, via protein kinase B/Akt and mTOR/p70s6k pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3β on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.

Original languageEnglish (US)
Pages (from-to)1535-1549
Number of pages15
JournalJournal of Clinical Investigation
Volume113
Issue number11
DOIs
StatePublished - Jun 2004

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Glycogen Synthase Kinase 3
Mitochondrial Swelling
Permeability
Cytoprotection
Cardiac Myocytes
Reactive Oxygen Species
Mitochondria
70-kDa Ribosomal Protein S6 Kinases
Proto-Oncogene Proteins c-akt
Receptor Protein-Tyrosine Kinases
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Oxidation-Reduction
Cell Survival
Cell Death
mitochondrial permeability transition pore

ASJC Scopus subject areas

  • Medicine(all)

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Glycogen synthase kinase-3β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore. / Juhaszova, Magdalena; Zorov, Dmitry B.; Kim, Suhn Hee; Pepe, Salvatore; Fu, Qin; Fishbein, Kenneth W.; Ziman, Bruce D.; Wang, Su; Ytrehus, Kirsti; Antos, Christopher L.; Olson, Eric N.; Sollott, Steven J.

In: Journal of Clinical Investigation, Vol. 113, No. 11, 06.2004, p. 1535-1549.

Research output: Contribution to journalArticle

Juhaszova, M, Zorov, DB, Kim, SH, Pepe, S, Fu, Q, Fishbein, KW, Ziman, BD, Wang, S, Ytrehus, K, Antos, CL, Olson, EN & Sollott, SJ 2004, 'Glycogen synthase kinase-3β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore', Journal of Clinical Investigation, vol. 113, no. 11, pp. 1535-1549. https://doi.org/10.1172/JCI200419906
Juhaszova, Magdalena ; Zorov, Dmitry B. ; Kim, Suhn Hee ; Pepe, Salvatore ; Fu, Qin ; Fishbein, Kenneth W. ; Ziman, Bruce D. ; Wang, Su ; Ytrehus, Kirsti ; Antos, Christopher L. ; Olson, Eric N. ; Sollott, Steven J. / Glycogen synthase kinase-3β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 11. pp. 1535-1549.
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