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. Weinberg; Hossein Ardehali

doi:10.1016/j.molcel.2022.02.028

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 journal › Article › peer-review

90 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	1261-1277.e9
Journal	Molecular cell
Volume	82
Issue number	7
DOIs	https://doi.org/10.1016/j.molcel.2022.02.028
State	Published - Apr 7 2022

Funding

We would like to thank Meng Shang and Eric Xia for managing our mouse colony and genotyping the mice used in this study. Thanks to Peng Gao from the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University for performing metabolomics mass spectrometry for our metabolomics experiments. We thank Young Ah Goo from the Northwestern University Proteomics Center of Excellence for running the mass spectrometry for our proteomics experiments. We thank Lynn Doglio and Pei-Ken from the Northwestern Transgenic and Targeted Mutagenesis for generating the ΔE1HK1 mice. Graphical abstract art was generated using modified images from SMART Servier Medical Art (Les Laboratoires Servier: https://smart.servier.com/ ). Funding for this work was provided through NRSA 5F31HL132552-04 awarded to A.D. and the Ledcuq Foundation and NHLBI HL127646 , HL140973 , and HL138982 awarded to H.A. B.T.L. is supported by the National Institutes of Health under award number, R01DK104927 , and Department of Veterans Affairs , Veterans Health Administration , Office of Research and Development , VA merit (grant no. 1I01BX003382 ). We would like to thank Meng Shang and Eric Xia for managing our mouse colony and genotyping the mice used in this study. Thanks to Peng Gao from the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University for performing metabolomics mass spectrometry for our metabolomics experiments. We thank Young Ah Goo from the Northwestern University Proteomics Center of Excellence for running the mass spectrometry for our proteomics experiments. We thank Lynn Doglio and Pei-Ken from the Northwestern Transgenic and Targeted Mutagenesis for generating the ?E1HK1 mice. Graphical abstract art was generated using modified images from SMART Servier Medical Art (Les Laboratoires Servier: https://smart.servier.com/). Funding for this work was provided through NRSA 5F31HL132552-04 awarded to A.D. and the Ledcuq Foundation and NHLBI HL127646, HL140973, and HL138982 awarded to H.A. B.T.L. is supported by the National Institutes of Health under award number, R01DK104927, and Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, VA merit (grant no. 1I01BX003382). Conceptualization, A.D. S.E.W. C.M.P. A.E.R. J.S. Shapiro, H.-C.C. B.T.L. and H.A.; methodology, A.D. C.M.P. A.E.R. I.B.-S. J.S. Shapiro, and H.-C.C.; investigation, A.D. C.M.P. F.K.-N. L.G. J.A.G. J.S. Stoolman, K.X. K.V.S. Y.C. C.C. K.P.S. P.J.S. and T.A.T.N.; results interpretation, H.A. A.D. C.M.P. J.S. Shapiro, and F.K.-N.; resources, B.T.L. I.B.-S. N.S.C. S.E.W. and H.A.; writing?original draft, H.A. A.D. and C.M.P.; writing?review and editing, C.M.P. J.S. Shapiro, F.K.-N. and H.A.; visualization, A.D.; supervision, S.E.W. B.T.L. and H.A.; funding acquisition, A.D. and H.A. The authors declare no competing interests.

Keywords

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

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2022.02.028

Cite this

De Jesus, A., Keyhani-Nejad, F., Pusec, C. M., Goodman, L., Geier, J. A., Stoolman, J. S., Stanczyk, P. J., Nguyen, T., Xu, K., Suresh, K. V., Chen, Y., Rodriguez, A. E., Shapiro, J. S., Chang, H. C., Chen, C., Shah, K. P., Ben-Sahra, I., Layden, B. T., Chandel, N. S., ... Ardehali, H. (2022). Hexokinase 1 cellular localization regulates the metabolic fate of glucose. Molecular cell, 82(7), 1261-1277.e9. https://doi.org/10.1016/j.molcel.2022.02.028

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title = "Hexokinase 1 cellular localization regulates the metabolic fate of glucose",

abstract = "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.",

keywords = "GAPDH, S-nitrosylation, hexokinase, inflammation, innate immunity, macrophage, metabolism, mitochondria, pentose phosphate pathway, subcellular localization",

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

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = apr,

day = "7",

doi = "10.1016/j.molcel.2022.02.028",

language = "English (US)",

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pages = "1261--1277.e9",

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De Jesus, A, Keyhani-Nejad, F, Pusec, CM, Goodman, L, Geier, JA, Stoolman, JS, Stanczyk, PJ, Nguyen, T, Xu, K, Suresh, KV, Chen, Y, Rodriguez, AE, Shapiro, JS, Chang, HC, Chen, C, Shah, KP, Ben-Sahra, I, Layden, BT, Chandel, NS , Weinberg, SE & Ardehali, H 2022, 'Hexokinase 1 cellular localization regulates the metabolic fate of glucose', Molecular cell, vol. 82, no. 7, pp. 1261-1277.e9. https://doi.org/10.1016/j.molcel.2022.02.028

TY - JOUR

T1 - Hexokinase 1 cellular localization regulates the metabolic fate of glucose

AU - De Jesus, Adam

AU - Keyhani-Nejad, Farnaz

AU - Pusec, Carolina M.

AU - Goodman, Lauren

AU - Geier, Justin A.

AU - Stoolman, Joshua S.

AU - Stanczyk, Paulina J.

AU - Nguyen, Tivoli

AU - Xu, Kai

AU - Suresh, Krishna V.

AU - Chen, Yihan

AU - Rodriguez, Arianne E.

AU - Shapiro, Jason S.

AU - Chang, Hsiang Chun

AU - Chen, Chunlei

AU - Shah, Kriti P.

AU - Ben-Sahra, Issam

AU - Layden, Brian T.

AU - Chandel, Navdeep S.

AU - Weinberg, Samuel E.

AU - Ardehali, Hossein

PY - 2022/4/7

Y1 - 2022/4/7

N2 - 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.

AB - 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.

KW - GAPDH

KW - S-nitrosylation

KW - hexokinase

KW - inflammation

KW - innate immunity

KW - macrophage

KW - metabolism

KW - mitochondria

KW - pentose phosphate pathway

KW - subcellular localization

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U2 - 10.1016/j.molcel.2022.02.028

DO - 10.1016/j.molcel.2022.02.028

M3 - Article

C2 - 35305311

AN - SCOPUS:85127503892

SN - 1097-2765

VL - 82

SP - 1261-1277.e9

JO - Molecular cell

JF - Molecular cell

IS - 7

ER -

Hexokinase 1 cellular localization regulates the metabolic fate of glucose

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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