HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate

HK1 and HK2 are increasingly recognized not only as glycolytic enzymes but also as key modulators of mitochondrial function and cell fate through dynamic interactions with VDAC. This review explores how HK-VDAC complexes support metabolic flexibility, regulate apoptosis, and coordinate glycolytic and mitochondrial activity across diverse physiological and pathological conditions. We incorporate recent reinterpretations of the Warburg effect, emphasizing how spatial and functional reorganization of HK supports proliferative metabolism beyond classical models of mitochondrial dysfunction. Importantly, the HK-VDAC interaction is dynamically regulated by post-translational modifications and signaling pathways that control its stability and mitochondrial anchoring. Disruption of these regulatory mechanisms can impair the balance between glycolytic and mitochondrial metabolism, contributing to disease progression. Emerging evidence links altered HK-VDAC interactions to the metabolic and apoptotic imbalances observed in cancer, neurodegeneration, and aging. By integrating insights from structural biology, bioenergetics, and disease models, we highlight mitochondrial HK anchoring as a central hub for metabolic adaptation and stress response.