Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Mol Cell. 2022 Apr 7;82(7):1261-1277.e9. doi: 10.1016/j.molcel.2022.02.028. Epub 2022 Mar 18.
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.
己糖激酶 (HK) 酶的产物葡萄糖-6-磷酸可通过糖酵解或定向到其他代谢途径（如戊糖磷酸途径 (PPP)）代谢，以生成合成代谢中间体。HK1 含有一个 N 端线粒体结合结构域 (MBD)，但其生理意义尚不清楚。为了阐明 HK1 线粒体解离对细胞代谢的影响，我们生成了缺乏 HK1 MBD（ΔE1HK1）的小鼠。这些小鼠在受到脂多糖刺激时会产生过度的炎症反应。此外，葡萄糖通量在 GAPDH 以下水平下降，而 PPP 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 iNOS 通过 GAPDH 亚硝基化。此外，来自低度炎症条件（如衰老和糖尿病）的人和小鼠巨噬细胞显示出胞质 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 来改变葡萄糖代谢。
