Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
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DOI：
10.1016/j.molcel.2022.02.028
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发表时间：
2022-04-07
期刊：
影响因子：
16
通讯作者：
Ardehali H
中科院分区：
文献类型：
--
作者：
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
己糖激酶 (HK) 的产物葡萄糖-6-磷酸可通过糖酵解进行代谢，或引导至其他代谢途径，例如磷酸戊糖途径 (PPP)，以产生合成代谢中间体。 HK1 包含 N 端线粒体结合域 (MBD)，但其生理意义仍不清楚。为了阐明 HK1 线粒体解离对细胞代谢的影响，我们培育了缺乏 HK1 MBD (ΔE1HK1) 的小鼠。当受到脂多糖的攻击时，这些小鼠产生了过度炎症反应。此外，低于 GAPDH 水平的葡萄糖通量减少，通过 PPP 的上游通量增加。 GAPDH 以下的糖酵解阻断是通过胞质 HK1 与 S100A8/A9 的结合介导的，导致 GAPDH 通过 iNOS 亚硝基化。此外，来自低度炎症（例如衰老和糖尿病）的人类和小鼠巨噬细胞表现出胞质 HK1 增加和 GAPDH 活性降低。我们的数据表明 HK1 线粒体结合通过调节 GAPDH 改变葡萄糖代谢。德耶稣等人。描述 HK1 亚细胞定位如何通过抑制 GAPDH 来调节其底物 G6P 在分解代谢和合成代谢之间的代谢命运。来自衰老和糖尿病模型的免疫细胞显示出更高水平的胞质 HK1 和增加的炎症
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 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. De Jesus et al. describe how HK1 subcellular localization regulates the metabolic fate of its substrate, G6P, between catabolic and anabolic metabolism through inhibition of GAPDH. Immune cells from models of aging and diabetes show higher levels of cytosolic HK1 and increased inflammation
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