Potassium ions promote hexokinase-II dependent glycolysis

Helmut Bischof; Sandra Burgstaller; Anna Springer; Lucas Matt; Thomas Rauter; Olaf A Bachkönig; Tony Schmidt; Klaus Groschner; Rainer Schindl; Tobias Madl; Nikolaus Plesnila; Robert Lukowski; Wolfgang F Graier; Roland Malli

doi:10.1016/j.isci.2021.102346

Potassium ions promote hexokinase-II dependent glycolysis

iScience. 2021 Mar 22;24(4):102346. doi: 10.1016/j.isci.2021.102346. eCollection 2021 Apr 23.

Authors

Helmut Bischof^{1

2}, Sandra Burgstaller^{1

3}, Anna Springer¹, Lucas Matt², Thomas Rauter¹, Olaf A Bachkönig¹, Tony Schmidt⁴, Klaus Groschner^{4

5}, Rainer Schindl^{4

5}, Tobias Madl^{1

5}, Nikolaus Plesnila^{6

7}, Robert Lukowski², Wolfgang F Graier^{1

5}, Roland Malli^{1

5}

Affiliations

¹ Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.
² Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
³ Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Auf der Morgenstelle 15, 72076 Tuebingen, Germany.
⁴ Gottfried Schatz Research Center, Biophysics, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.
⁵ BioTechMed-Graz, Mozartgasse 12/II, 8010 Graz, Austria.
⁶ Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany.
⁷ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Abstract

High expression levels of mitochondria-associated hexokinase-II (HKII) represent a hallmark of metabolically highly active cells such as fast proliferating cancer cells. Typically, the enzyme provides a crucial metabolic switch towards aerobic glycolysis. By imaging metabolic activities on the single-cell level with genetically encoded fluorescent biosensors, we here demonstrate that HKII activity requires intracellular K⁺. The K⁺ dependency of glycolysis in cells expressing HKII was confirmed in cell populations using extracellular flux analysis and nuclear magnetic resonance-based metabolomics. Reductions of intracellular K⁺ by gramicidin acutely disrupted HKII-dependent glycolysis and triggered energy stress pathways, while K⁺ re-addition promptly restored glycolysis-dependent adenosine-5'-triphosphate generation. Moreover, expression and activation of K_V1.3, a voltage-gated K⁺ channel, lowered cellular K⁺ content and the glycolytic activity of HEK293 cells. Our findings unveil K⁺ as an essential cofactor of HKII and provide a mechanistic link between activities of distinct K⁺ channels and cell metabolism.

Keywords: Biochemical Mechanism; Biochemistry; Molecular Physiology.

Abstract

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