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

Abstract

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.

Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators

“…S1, Table S1 ). Inspection of the density map showed clear densities for the VSDs, the channel pore domain, the cytoplasmic T1 domains, and the caveolin-binding domains 46 ( Fig. 1A, 1B, Fig.…”

Routes for Potassium Ions across Mitochondrial Membranes: A Biophysical Point of View with Special Focus on the ATP-Sensitive K+ Channel

“…With the exception of HCNs and ROMK2 (see below), bioinformatic tools do not predict mitochondrial localization due to the lack of a typical N-terminal mitochondria-targeting sequence. Our recent data indicate that, for example, in the case of Kv1.3, association of the channel with caveolin-1 promotes PM targeting, while the lack of such functional coupling causes accumulation of the channel in mitochondria, with severe consequences on mitochondrial function and cell survival [40]. Whether association with caveolin may play a role in channel trafficking and subcellular targeting also in the case of other K + channels is an interesting point for future investigation.…”

The Mitochondrial Routing of the Kv1.3 Channel

“…Rat Kv1.3 and human Kv1.5 channels and the mitochondrial marker have been widely described by our laboratory (18,19,23,24). Rat Kv1.1, Kv1.2 and Kv1.4 channels in pGEM7 were obtained from M. M. Tamkun (Colorado State University, CO).…”

“…Furthermore, mitoBK Ca channels translocate to the IMM through alternative splicing at the C-terminus of KCa1.1. However, alternative splicing mechanisms are not unique because uniexonic voltage-gated potassium channels of the Shaker family, such as Kv1.1, Kv1.3 and Kv1.5, target the IMM (17)(18)(19). On the other hand, the mitochondrial sorting of Kesv, a viral K + channel with only two transmembrane segments, depends on unidentified signals within the C-terminal transmembrane hydrophobic domain that are recognized by the TIM/TOM complex (20).…”

“…In addition, mitoKv1.3 controls cell cycle progression by regulating mitochondrial dynamics (18). Factors determining the equilibrium between PM and mitochondrial Kv1.3 are scarcely known (19), although knowledge of these factors would be essential to understand the pathophysiology of many processes involved in human Kv1.3related illnesses, such as cancer, autoimmune diseases and obesity (22).…”