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Editorial
. 2008 Oct 24;103(9):910-3.
doi: 10.1161/01.RES.0000338259.37472.b6.

Overcoming an energy crisis?: an adaptive role of glycogen synthase kinase-3 inhibition in ischemia/reperfusion

Peiyong Zhai, Junichi Sadoshima
Editorial

Overcoming an energy crisis?: an adaptive role of glycogen synthase kinase-3 inhibition in ischemia/reperfusion

Peiyong Zhai et al. Circ Res. .
No abstract available

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Figures

Figure
Figure
The ATP generated through anaerobic glycolysis can be transported through voltage dependent anion channels (VDACs)- and adenine nucleotide translocase (ANT)-dependent mechanisms into the mitochondrial matrix, where it is hydrolyzed by F1F0-ATPase acting at the reverse mode. GSK-3 interacts with VDAC and increases its phosphorylation, which in turn likely facilitates ATP transport across the outer mitochondrial membrane (OMM). GSK-3 inhibitors and/or GSK-3 phosphorylation by upstream kinases decrease VDAC phosphorylation through inhibition of GSK-3 kinase activity and/or dissociating GSK-3 from VDAC. Dephosphorylation of VDAC in turn may reduce ATP transport by directly decreasing VDAC conductance of ATP or by indirectly enhancing interaction of VDAC with Bcl-2 resulting in decreased mitochondrial consumption of ATP. The reduced ATP consumption decreases the mitochondrial membrane potential, thereby alleviating Ca2+ overload and oxidative stress. GSK-3 and phospho-GSK-3 may be translocated through translocase of outer membrane 20 (TOM20) from the cytoplasm to intermembrane space, where they interact with ANT located in the inner mitochondrial membrane (IMM). The interaction between phospho-GSK-3 and ANT dissociates cyclopholin-D from ANT, thereby regulating mPTP (not shown). GSK-3 increases degradation of hypoxia-inducible factor 1α (HIF-1α), which facilitates glycolysis, . Inhibition of GSK-3 stabilizes HIF-1α and thus promotes ATP generation by enhancing anaerobic glycolysis. Dashed arrows indicates translocation of molecules.
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