TY - JOUR
T1 - Glycogen synthase kinase-3β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore
AU - Juhaszova, Magdalena
AU - Zorov, Dmitry B.
AU - Kim, Suhn Hee
AU - Pepe, Salvatore
AU - Fu, Qin
AU - Fishbein, Kenneth W.
AU - Ziman, Bruce D.
AU - Wang, Su
AU - Ytrehus, Kirsti
AU - Antos, Christopher L.
AU - Olson, Eric N.
AU - Sollott, Steven J.
PY - 2004/6
Y1 - 2004/6
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI19906
DO - 10.1172/JCI19906
M3 - Article
C2 - 15173880
AN - SCOPUS:85047692700
SN - 0021-9738
VL - 113
SP - 1535
EP - 1549
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -