Hexokinase 1 cellular localization regulates the metabolic fate of glucose

Adam De Jesus, Farnaz Keyhani-Nejad, Carolina M. Pusec, Lauren Goodman, Justin A. Geier, Joshua S. Stoolman, Paulina J. Stanczyk, Tivoli Nguyen, Kai Xu, Krishna V. Suresh, Yihan Chen, Arianne E. Rodriguez, Jason S. Shapiro, Hsiang Chun Chang, Chunlei Chen, Kriti P. Shah, Issam Ben-Sahra, Brian T. Layden, Navdeep S. Chandel, Samuel E. WeinbergHossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

Original languageEnglish (US)
Pages (from-to)1261-1277.e9
JournalMolecular cell
Issue number7
StatePublished - Apr 7 2022


  • S-nitrosylation
  • hexokinase
  • inflammation
  • innate immunity
  • macrophage
  • metabolism
  • mitochondria
  • pentose phosphate pathway
  • subcellular localization

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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