Mitochondria and GSK-3β in Cardioprotection Against Ischemia/Reperfusion Injury

Abstract

The mitochondrion is a powerhouse of the cell, a platform of cell signaling and decision-maker of cell death, including death by ischemia/reperfusion. Ischemia shuts off ATP production by mitochondria, and cell viability is compromised by energy deficiency and build-up of cytotoxic metabolites during ischemia. Furthermore, the mitochondrial permeability transition pore (mPTP) is primed by ischemia to open upon reperfusion, leading to reperfusion-induced cell necrosis. mPTP opening can be suppressed by ischemic preconditioning (IPC) and other interventions that induce phosphorylation of GSK-3beta. Activation of the mitochondrial ATP-sensitive K(+) channel (mK(ATP) channel) is an important signaling step in a trigger phase of IPC, which ultimately enhances GSK-3beta phosphorylation upon reperfusion, and this channel functions as a mediator of cytoprotection as well. The mitochondrial Ca(2+)-activated K(+) channel appears to play roles similar to those of the mK(ATP) channel, though regulatory mechanisms of the channels are different. Phosphorylated GSK-3beta inhibits mPTP opening presumably by multiple mechanisms, including preservation of hexokinase II in mPTP complex, prevention of interaction of cyclophilin-D with adenine nucleotide translocase, inhibition of p53 activation and attenuation of ATP hydrolysis during ischemia. However, cytoprotective signaling pathways to GSK-3beta phosphorylation and other mPTP regulatory factors are modified by co-morbidities, including type 2 diabetes, and such modification makes the myocardium refractory to IPC and other cardioprotective agents. Regulatory mechanisms of mPTP, and their alterations by morbidities frequently associated with ischemic heart disease need to be further characterized for translation of mitochondrial and mPTP biology to the clinical arena.

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This may contribute to higher susceptibility to mPTP opening (Marzetti et al., 2008) and to the reduction in affinity of ANT for CypD. An increased phospho‐GSK‐3β binding to ANT was suggested to be responsible for the inhibition of mPTP opening (Miura & Tanno, 2010; Nishihara et al., 2007). This mechanism would contribute to the cardioprotective effect of several drugs such as formononetin or resveratrol and of ischemic preconditioning (Cheng, Xia, Han, & Rong, 2016; Xi, Wang, Mueller, Norfleet, & Xu, 2009; Zhu, Rebecchi, Glass, Brink, & Liu, 2013; Zhu, Rebecchi, Wang, et al., 2013).…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…The phosphorylation of p53 by GSK-3β is essential for its acetylation and subsequent translocation into mitochondria [67]. It has been demonstrated that p53-regulated mPTP opening can be abrogated by GSK-3β inhibition [68]. …”

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver

“…MPT induction can be suppressed by IPC and other interventions that increase phosphoSer 9 -GSK-3β [3,23,[40][41][42][43]. GSK-3β is an important regulator of cell function, controlling gene expression, cell cycle, survival, and apoptosis [44][45][46]. Upon reperfusion, phospho-Ser 9 -GSK-3β in mitochondria physically interacts with the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), thus impairing the interaction of the ANT with cyclophilin D (CypD), elevating the threshold for MPT induction [40,42,46,47].…”