Myeloid Cell Leukemia 1 and Hexokinase 2 Directly Interact to Form a Glucose Metabolic Regulatory Axis

Hexokinase 2 (HK2) catalyzes the first committed step of glucose metabolism - the conversion of glucose to glucose-6-phosphate – directing carbon flux into an array of metabolic pathways such as glycolysis, pentose phosphate pathway, amino acid biosynthesis and others. Given its prominent role in glucose metabolism, it is critical we understand the regulation of HK2 to appreciate its role in normal physiological function as well as disease states like cancers. Herein we establish a fundamental link between cell survival mechanism and metabolic regulation by demonstrating myeloid cell leukemia 1 (MCL1) directly binds and enhances HK2 enzymatic activity through interactions with reverse Bcl-2 homology motifs (rBH3) on HK2. Consequently, we observe significant reductions in glucose-derived metabolites and impaired cellular metabolic plasticity with disruption of the HK2-MCL1 interaction. These findings establish a novel mechanism by which anti-apoptotic proteins can directly regulate glucose metabolism.