A novel mitochondrial Kv1.3-caveolin axis controls cell survival and apoptosis

The voltage-gated potassium channel Kv1.3 plays an apparent dual
physiological role by participating in activation and proliferation of
leukocytes as well as promoting apoptosis in several types of tumor cells.
Therefore, Kv1.3 is considered a potential pharmacological target for
immunodeficiency and cancer. Different cellular locations of Kv1.3, at the
plasma membrane or the mitochondria, could be responsible for such
duality. While plasma membrane Kv1.3 facilitates proliferation, the
mitochondrial channel modulates apoptotic signaling.  Several
molecular determinants of Kv1.3 drive the channel to the cell surface, but
no information is available about its mitochondrial targeting. Caveolins,
which are able to modulate cell survival, participate in the plasma
membrane targeting of Kv1.3. The channel, via a caveolin-binding domain
(CDB), associates with caveolin 1 (Cav1), which localizes Kv1.3 to lipid
raft membrane microdomains. The aim of our study was to understand the
role of such interactions not only for channel targeting but also for cell
survival in mammalian cells. By using a caveolin association-deficient
channel (Kv1.3 CDBless), we demonstrate here that while the Kv1.3-Cav1
interaction is responsible for the channel localization in the plasma
membrane, a lack of such interaction accumulates Kv1.3 in the
mitochondria. Kv1.3 CDBless severely affects mitochondrial physiology and
cell survival, indicating that a functional link of Kv1.3 with Cav1 within
the mitochondria modulates the pro-apoptotic effects of the channel.
Therefore, the balance exerted by these two complementary mechanisms
fine-tune the physiological role of Kv1.3 during cell survival or
apoptosis. Our data highlight an unexpected role for the mitochondrial
caveolin-Kv1.3 axis during cell survival and apoptosis.