The role of small conductance calcium-activated potassium channels in mitochondrial dysfunction: Targeting metabolic reprogramming and calcium homeostasis

Neurodegenerative diseases are characterized by progressive cell death, often attributed to mitochondrial dysfunction, inflammation and oxidative stress. The main aim of this thesis was to investigate the role of SK channels on calcium homeostasis, reactive oxygen species (ROS) and mitochondrial metabolism, in neurodegenerative conditions, inflammation and brain cancer. We showed that pharmacologically modulating mitochondrial KCa channels mediates cellular protection against oxidative stress through mitochondrial preconditioning in neurodegenerative conditions. Investigating the role of mitochondrial calcium in oxidative stress, we demonstrated that an enhanced endoplasmic reticulum – mitochondrial interface induced mitochondrial calcium overload in conditions of oxidative stress, and impaired mitochondrial bioenergetics, events that were prevented by SK channel activator CyPPA. Further, we showed that attenuation of mitochondrial calcium uptake using mitoxantrone and ruthenium red preserved cell viability in ferroptosis. Thus, attenuation of mitochondrial calcium, in particular via activation of SK channels, plays a crucial role in cellular protection against oxidative stress.
Neuroprotective effects of SK channel activation against ferroptosis also involve adaptations in cellular metabolism. CyPPA induced an initial metabolic shift towards glycolysis, followed by a small reduction in mitochondrial complex activity and a mild induction of mitochondrial ROS. In vivo, CyPPA increased lactate production, median lifespan and mitochondrial stress resistance. Besides, CyPPA attenuated LPS-induced macrophage activation, even in conditions potentiated by succinate, possibly via reducing reverse electron transfer.
Finally, we reported that SK channel activation can promote anti-tumour capacities of the classical anti-cancer agent auranofin in brain cancer cells, due to enhancing ROS levels and mitochondrial dysfunction.