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

Citation

Felipe, Antonio et al. (2021), A novel mitochondrial Kv1.3-caveolin axis controls cell survival and apoptosis, Dryad, Dataset, https://doi.org/10.5061/dryad.mcvdnck13

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.

Methods

Data was collected from independent experiments performed in each laboratory partner. All techniques are been freely accessible and descriptions and procedures are fully included in materials and methods section of the related manuscript.

Funding

Ministerio de Ciencia e Innovación, Award: BFU2017-87104-R

Ministerio de Ciencia e Innovación, Award: PID2020-112647RB-I00

Ministerio de Ciencia e Innovación, Award: CSD2008-00005

Associazione Italiana per la Ricerca sul Cancro, Award: AIRC IG grant 20286

Italian Ministry of University and Education, Award: PRIN 20174TB8KW_004

Italian Association for Multiple Sclerosis

European Regional Development Fund

Italian Ministry of University and Education, Award: PRIN 20174TB8KW_004

Italian Association for Multiple Sclerosis