Cell Death and Disease (Apr 2021)

Kv1.3 voltage-gated potassium channels link cellular respiration to proliferation through a non-conducting mechanism

  • Faye L. Styles,
  • Moza M. Al-Owais,
  • Jason L. Scragg,
  • Eulashini Chuntharpursat-Bon,
  • Nishani T. Hettiarachchi,
  • Jonathan D. Lippiat,
  • Aisling Minard,
  • Robin S. Bon,
  • Karen Porter,
  • Piruthivi Sukumar,
  • Chris Peers,
  • Lee D. Roberts

DOI
https://doi.org/10.1038/s41419-021-03627-6
Journal volume & issue
Vol. 12, no. 4
pp. 1 – 14

Abstract

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Abstract Cellular energy metabolism is fundamental for all biological functions. Cellular proliferation requires extensive metabolic reprogramming and has a high energy demand. The Kv1.3 voltage-gated potassium channel drives cellular proliferation. Kv1.3 channels localise to mitochondria. Using high-resolution respirometry, we show Kv1.3 channels increase oxidative phosphorylation, independently of redox balance, mitochondrial membrane potential or calcium signalling. Kv1.3-induced respiration increased reactive oxygen species production. Reducing reactive oxygen concentrations inhibited Kv1.3-induced proliferation. Selective Kv1.3 mutation identified that channel-induced respiration required an intact voltage sensor and C-terminal ERK1/2 phosphorylation site, but is channel pore independent. We show Kv1.3 channels regulate respiration through a non-conducting mechanism to generate reactive oxygen species which drive proliferation. This study identifies a Kv1.3-mediated mechanism underlying the metabolic regulation of proliferation, which may provide a therapeutic target for diseases characterised by dysfunctional proliferation and cell growth.