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/p70 s6k 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.

PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury

“…The observation that BD110 increased GSK3β phosphorylation without an increase in Akt activation raises the possibility that these pathways may also phosphorylate GSK3β, previously proposed to act as a central integrator of survival signaling (43,44). For example, SGK1 is a PI3K-dependent serine-threonine kinase that can phosphorylate GSK3β and promote survival in cardiomyocytes (19).…”

Curcumin-Mediated Neuroprotection Against Amyloid-β-Induced Mitochondrial Dysfunction Involves the Inhibition of GSK-3β

“…GSK-3␤ is suggested to be involved in the intracellular ROS generation when activated, and GSK-3␤'s inhibitors inhibit ROS production, promote mitochondrial biogenesis, and prevent mitochondrial apoptosis [31][32][33]. Inhibition of GSK-3␤ is suggested to prevent mitochondrial damage by inhibiting the mitochondrial permeability transition pore (mPTP) opening [34,35]. We suppose that GSK-3␤ may also be involved in the protection of curcumin on A␤-induced mitochondrial oxidative damage.…”

“…Recently, GSK-3␤ has been suggested to act on a mitochondrial target and is possibly associated with mitochondrial components of the mPTP. GSK-3␤ may also be involved in intracellular ROS generation when activated, which may link to the inhibitory opening of mPTP [34,35]. GSK-3␤ inhibitor SB-415286 decreases GSK-3␤ activation and down-regulates intracellular ROS.…”

Mitochondrial membrane potential

“…In addition, it is a very efficient photosensitizer which makes not easily interpretable results on the appearance in a single mitochondrial filament of regions with J-aggregates [131] which could be a result of a photodamage associated with mitochondrial segregation and fission [108]. However, most, if not all mitochondrial fluorescent probes suffer from the same critique of being unwanted photosensitizers which sometimes can be exploited [49,134]. Therefore, these probes must be used carefully with the minimal light exposure to minimize photo-generated ROS toxicity.…”