HEXOKINASE 1 SUBCELLULAR LOCALIZATION REGULATES THE METABOLIC FATE OF GLUCOSE
PublicThe product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative pathways, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal domain that permits mitochondrial binding, but its physiologic significance remains unclear. We generated mice lacking the HK1 mitochondrial-binding domain. These mice have no overt phenotype, but display increased glucose flux through the PPP, decreased flux below the level of GAPDH, and a hyper-inflammatory response to lipopolysaccharide. The mechanism for the increased PPP flux is through glycolytic block at GAPDH, which is mediated by binding of cytosolic HK1 with S100A8/A9 and increased GAPDH nitrosylation through iNOS. Tissues from mice with conditions of low-grade inflammation, such as aging and diabetes, display increased cytosolic HK1 and cytokine production, along with reduced GAPDH activity. Our data indicate that HK1 mitochondrial-binding alters glucose fate and induces a pro-inflammatory response through regulation of GAPDH.
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DeJesus_northwestern_0163D_15348.pdf | 2021-02-01 | Public |
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