Mitochondrial Potassium Channels as Determinants of Cell Fate

Mitochondria play a central role in various pathophysiological processes ranging from ageing to cardiac disease, inflammation, neurodegeneration, cell death and cancer. The mitochondrial outer and inner membranes both harbor a plethora of ion channels with different selectivity and function. Many of these channels, by modulating mitochondrial energy metabolism, membrane potential and reactive oxygen production, are emerging as important participants in life-and-death decisions of the cell. Several potassium channels, for example mitoKv1.3, mitoIKCa and mitoTASK-3, are highly expressed in cancer cell mitochondria. We are developing new pharmacological tools to control the function of various potassium channels present in the inner mitochondrial membrane with the aim of inducing apoptosis of cancer cells, while leaving healthy cells unaffected. According to our results, combination of specific, novel mitochondria-targeted channel inhibitors may become a promising strategy against poor-prognosis cancers such as pancreatic ductal adenocarcinoma and triple negative breast cancer and to kill cancer stem cells. On the other hand, activation of some mitochondrial potassium channels such as mitoK Ca and mitoK ATP can protect cells against ischemic damage. The role of mitoK ATP versus plasmamembrane-located K ATP channel in this protection as well as its molecular identity however are still debated. Reconstitution of a mitochondria-specific cation channel together with a mitochondria-located Sulphonylurea Receptor gives rise to a channel activity whose biophysical and pharmacological profiles strongly resemble the characteristics of mitoK ATP. Activation of this channel modulates mitochondrial physiology and cell fate. Altogether, mitochondrial potassium channels are important pharmacological targets both in the context of cancer and ischemia