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Potassium ions promote hexokinase-II dependent glycolysis.

iScience. 2021 Mar 22;24(4):102346. doi: 10.1016/j.isci.2021.102346. PMID: 33870140; PMCID: PMC8047173.

Authors/Editors: Bischof H, Burgstaller S, Springer A, Matt L, Rauter T, Bachkönig OA, Schmidt T, Groschner K, Schindl R, Madl T, Plesnila N, Lukowski R, Graier WF, Malli R.
Publication Date: 2021

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 KV1.3, 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.

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