Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore
Magdalena Juhaszova, … , Eric N. Olson, Steven J. Sollott
Magdalena Juhaszova, … , Eric N. Olson, Steven J. Sollott
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1535-1549. https://doi.org/10.1172/JCI19906.
View: Text | PDF
Article Cell biology

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

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.

Authors

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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Mechanisms of protection. (A) MPT susceptibility to ROS (tMPT) can be re...
Mechanisms of protection. (A) MPT susceptibility to ROS (tMPT) can be regulated by the mitoKATP: role of PKC. *P < 0.001 vs. control (Con). (B) Activation of distinct protection pathways improves cell survival to a similar degree in the hypoxia/reoxygenation protocol used to assess tMPT. Hypoxia/reoxygenation groups included treatment with cyclosporin A, Hoe, Li+, Dz, and PC. The protective effect of Dz is abolished by 5HD (inset). **P < 0.02. (C) Translocation of εPKC toward mitochondria, induced by mitoKATP activation. The panels on the left represent immunostained cardiac myocytes (15 ∞ 15 ∝m2 region surrounding the nucleus, shown for technical consistency). The immunoblot on the right shows that both Dz and PMA induce εPKC translocation from the soluble to the membranous cellular fraction. (D) Transmission electron microscopy of immunogold-labeled εPKC in a cardiac myocyte from a heart treated with PMA (100 nM, 15 minutes), demonstrating mitochondrial membrane localization (right middle panel; dashed circle outlines a mitochondrial profile); immunolabeling is absent in control (not shown). (E) ROS-induced PKC translocation toward mitochondria. Photoexcitation-mediated MPT induction in an approximately 10 ∞ 10 ∝m2 region in TMRM-loaded cardiac myocytes (middle panels, red), and εPKC immunostaining (top panels, green) in the same cells. The right panels show effects of the ROS scavenger NAC. The bottom panels compare the εPKC labeling through the photoexcited regions.