Mitochondrial dynamics control of mitoKv1.3 during cell cycle progression.

Abstract

The voltage-gated potassium channel Kv1.3 plays a crucial role in adipose tissue. Kv1.3 is involved in the development of obesity and diabetes, thus becoming a potential therapeutical target. Kv1.3 locates at the plasma membrane and at mitochondria, controlling cell proliferation and differentiation or apoptosis, respectively. While the plasma membrane targeting is by a COPII-dependent mechanism and driven by several forward-traffic motifs, little is known about the mitochondrial route. In this work, the mitochondrial Kv1.3 interactome was obtained in order to decipher the mitochondrial components that participate in mitoKv1.3 import pathway. We report for the first time that, although Kv1.3 is a multispanning protein with no defined N-terminal presequence, the channel follows an unconventional routing through the TIM23 complex. The targeting is mediated by the information encoded along the channel sequence and regulated by the cytosolic Hsp70/90 chaperon complex. Once in mitochondria, mitoKv1.3 shows a higher affinity for perinuclear populations. In addition, mitoKv1.3 expression is cell cycle-dependent, increasing at the G1/S phase. The development of a knocked-down preadipocyte cell line let us describe that Kv1.3 promotes the preadipocyte proliferation by regulating mitochondrial dynamics. Throughout the cell cycle, there are several fusion-fission events that are key for a correct proliferation. We found that Kv1.3 expression mediates the G1/S phase hyperfusion and, consequently, the hyperpolarization of mitochondria. Our results unravel the unconventional import pathway of Kv1.3 into the inner mitochondrial membrane. Moreover, it sheds light into Kv1.3 control of mitochondrial morphology and dynamics at the G1 phase fine-tuning proliferation. Supported by the Ministerio de Ciencia e Innovación (MICINN/AEI), Spain (PID2020-112647RB-I00 and 10.13039/501100011033) and European Regional Development Fund (FEDER).