SK2 channels regulate mitochondrial respiration and mitochondrial Ca²⁺ uptake

Mitochondrial calcium ([Ca²⁺]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca²⁺] m uptake upon SK channel activation as detected by time lapse mitochondrial Ca²⁺ measurements with the Ca²⁺-binding mitochondria-targeted aequorin and FRET-based [Ca²⁺] m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca²⁺] m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.