Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

Abstract

The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.

Characterization of endogenous Kv1.3 channel isoforms in T cells.

“…Furthermore, no differences in apoptosis induction were found in our clones when comparing WT with SF or KO after treatment with staurosporin, suggesting that Kv1.3 does not play a role in apoptosis in these cells. While this result is consistent with previously published studies in adipocytes (191), some authors claim that inhibition of Kv1.3 in cancer cells promotes apoptosis (70,72).…”

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).…”

“…MitoKv1.3 is linked to the control of apoptosis through a Bax-dependent mechanism, with important repercussions for anticancer therapy (21). 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).…”

The Phosphorylation of Kv1.3: A Modulatory Mechanism for a Multifunctional Ion Channel

“…Because the altered expression of Kv1.3 correlates with several types of tumors and cancer cells, this protein is widely considered to be an important anticancer target [18][19][20]. Kv1.3 is involved in a plethora of biological events, such as cell proliferation, activation, apoptosis, volume control, and tumorigenesis [21,22]. This review compiles all studies addressing Kv1.3 channel phosphorylation, from the very first observation reported to the most recent advances.…”