Fig. 7: Activation of SK channels prevents ferroptotic cell death. | Cell Death & Disease

Fig. 7: Activation of SK channels prevents ferroptotic cell death.

From: SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Fig. 7

Erastin blocks the Cys/Glu antiporter (XCT) in the plasma membrane leading to loss of glutathione (GSH) and glutathione peroxidase 4 (GPX4) activity. This enhances the oxidation of lipids by 12/15-lipoxygenases (12/15LOX), increasing ROS levels, promoting mitochondrial Ca2+ influx and increased ROS levels. Furthermore, ER wraps around mitochondria and initiates mitochondrial fragmentation, concomitant with the recruitment of dynamin-related protein 1 (DRP1) at the mitochondria to trigger mitochondrial fission. Activation of SK channels by CyPPA slightly decreases mitochondrial complex I activity and induces a mild increase in mitochondrial ROS levels. This leads to preconditioning effects, resulting in attenuation of ROS levels in conditions of oxidative stress. However, in the presence of MnTBAP, ROS are scavenged and this reduces the CyPPA-induced protection. In addition, CyPPA increases lactate production, which contributes to the observed protection. DCA promotes pyruvate to enter the citric cycle and facilitate more OXPHOS, thereby attenuating the CyPPA effect on glycolysis. Thus, opening of SK channels contribute to cell survival by increasing glycolytic activity and preventing mitochondrial damage.

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