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-3 (GSK-3).Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3, via protein kinase B/Akt and mTOR/p70 s6k pathways, PKC pathways, or protein kinase A pathways.The convergence of these pathways via inhibition of GSK-3 on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.Nonstandard abbreviations used: bisindolylmaleimide I (BIS); 2-chloro-N6-cyclopentyladenosine (CCPA); diazoxide (Dz); 2,7-dichlorodihydrofluorescein diacetate (DCF); glucagon-like peptide-a (GLP-1); glycogen synthase kinase-3 (GSK-3); 5-hydroxydecanoate (5HD); indanyloxyacetic acid 94 (IAA94); mitochondrial ATPdependent K + channel (mitoKATP); mitochondrial permeability transition (MPT); N-acetyl-L-cysteine (NAC); partial fatty acid oxidation (PFAO); Na/H exchange (NHE); preconditioning (PC); protein kinase A (PKA); protein kinase B (PKB); reactive oxygen species (ROS); receptor for activated C kinase (RACK); Sanglifehrin A (SFA); short interfering RNA (siRNA); S-nitroso-N-acetyl-penicillamine (SNAP); tetramethylrhodamine methyl ester (TMRM); transgenic (TG); transmembrane potential (); trimetazidine (TMZ); Tyr-D-Ala-Gly-Phe-D-Leu (DADLE).