Kv1.3 channels in mitochondria: A key coupling in cellular proliferation?

The Kv1.3 channel increases cellular proliferation and migration in multiple cell types. Various mechanisms have been proposed to explain how the channel stimulates proliferation, but the topic remains controversial. Previously thought to be localised only to the plasma membrane, the channel has been found in the inner mitochondrial membrane. In cancer, mitochondrial Kv1.3 may regulate apoptosis, yet the role of mitochondrial Kv1.3 in non-pathophysiological states remains less well defined. Cellular proliferation has a high energy demand, requiring ATP for processes like signal transduction to DNA, RNA and protein synthesis. The distinct energy requirements of cellular proliferation coupled with the known mitochondrial localization of Kv1.3 may mean that the Kv1.3 channel links cellular energy metabolism to proliferation. This thesis investigates whether the mitochondrial Kv1.3 channel is an anti-proliferative target in HEK293/Kv1.3 cells. Overexpression of Kv1.3 in HEK293 cells increased glycolysis, mitochondrial membrane potential, oxidative phosphorylation, reactive oxygen species, non-mitochondrial respiration and proliferation. Inhibition of mitochondrial Kv1.3 channels with 100nM PAPTP reduced respiration and proliferation. Inhibition of ROS with 5µM MitoQ reduced proliferation. Kv1.3 pore mutants determined that the voltage sensor, as well as the tyrosine 447 residue on the C-terminal of the Kv1.3 channel, are needed to stimulate respiration in HEK293 cells. Mitochondrial Kv1.3 channels were also found in primary human saphenous vein smooth muscle cells. Upregulation of Kv1.3 drives pathological proliferation of vascular smooth muscle cells in conditions like atherosclerosis and hypertension, and these cells also have altered metabolism. This data shows that the mitochondrial Kv1.3 channel directly increases oxidative phosphorylation, non-mitochondrial respiration and proliferation in HEK293 cells, providing a novel link between mitochondrial Kv1.3 and cellular energy homeostasis. Although the exact mechanisms are unclear, these data suggest that mitochondrial Kv1.3, especially it’s ion conduction independent properties, is a valid target for future research into Kv1.3 induced proliferation in VSMCs.