Codocedo Juan F, Landreth Gary E
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Immunometabolism (Cobham). 2022 Oct 28;4(4):e00011. doi: 10.1097/IN9.0000000000000011. eCollection 2022 Oct.
Hexokinases (HKs) catalyze the first and irreversible step of glucose metabolism. Its product, glucose-6-phosphate (G-6P) serves as a precursor for catabolic processes like glycolysis for adenosine 5'-triphosphate (ATP) production and anabolic pathways including the pentose phosphate pathway (PPP) for the generation of intermediaries like nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-P. Thus, the cellular fate of glucose is important not only for growth and maintenance, but also to determine different cellular activities. Studies in immune cells have demonstrated an intimate linkage between metabolic pathways and inflammation, however the precise molecular mechanisms that determine the cellular fate of glucose during inflammation or aging are not completely understood. Here we discuss a study by De Jesus et al that describes the role of HK1 cytosolic localization as a critical regulator of glucose flux by shunting glucose into the PPP at the expense of glycolysis, exacerbating the inflammatory response of macrophages. The authors convincingly demonstrate a novel mechanism that is independent of its mitochondrial functions, but involve the association to a protein complex that inhibits glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase. We expand the discussion by comparing previous studies related to the HK2 isoform and how cells have evolved to regulate the mitochondrial association of these two isoforms by non-redundant mechanism.
己糖激酶（HKs）催化葡萄糖代谢的第一步且是不可逆的步骤。其产物葡萄糖-6-磷酸（G-6P）是分解代谢过程（如用于生成三磷酸腺苷（ATP）的糖酵解）和合成代谢途径（包括用于生成烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和5-磷酸核酮糖等中间产物的磷酸戊糖途径（PPP））的前体。因此，葡萄糖的细胞命运不仅对细胞生长和维持很重要，而且对于决定不同的细胞活动也很重要。在免疫细胞中的研究表明代谢途径与炎症之间存在密切联系，然而，在炎症或衰老过程中决定葡萄糖细胞命运的精确分子机制尚未完全了解。在此，我们讨论德赫苏斯等人的一项研究，该研究描述了HK1胞质定位通过将葡萄糖分流至PPP而牺牲糖酵解，从而作为葡萄糖通量的关键调节因子，加剧巨噬细胞的炎症反应。作者令人信服地证明了一种新机制，该机制独立于其线粒体功能，但涉及与一种在3-磷酸甘油醛脱氢酶水平抑制糖酵解的蛋白质复合物的关联。我们通过比较先前与HK2亚型相关的研究以及细胞如何通过非冗余机制进化来调节这两种亚型的线粒体关联来扩展讨论。
