Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress

• DOI: 10.1016/j.molcel.2024.06.009
• Publication Date: 2024-07-08T14:36:50Z
• Authors: Johannes Pilic; Benjamin Gottschalk; Benjamin Bourgeois; Hansjörg Habisch; Zhanat Koshenov; Furkan E. Oflaz; Yusuf C. Erdogan; Seyed M. Miri; Esra N. Yiğit; Mehmet Ş. Aydın; Gürkan Öztürk; Emrah Eroglu; Varda Shoshan-Bar...; Tobias Madl; Wolfgang F. Graier; Roland Malli
• Keywords: Dynamins; 0301 basic medicine; 570; Citric Acid Cycle; Glucose-6-Phosphate; 612; Endoplasmic Reticulum; Mitochondrial Dynamics; GTP Phosphohydrolases; Mitochondrial Proteins; Mice; 03 medical and health sciences; Adenosine Triphosphate; Stress, Physiological; Hexokinase; Live-Cell Imaging; Humans; Animals; Protein Cluster; Mitochondrial Constriction; ER-Mitochondria Contact Sites; Energy Stress; Membrane Proteins; Glucose Starvation; Mitochondria; HEK293 Cells; Mutation; Mitochondrial Fission; Energy Metabolism; Glycolysis; Non-Catalytic Functions; HeLa Cells

Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.