Student National Taiwan University Taipei, Taipei, Taiwan (Republic of China)
Abstract: Glycogen, a primary energy reserve in mammals, depends on precise regulation by metabolic enzymes. While disruptions in canonical glycogen-associated proteins are well-documented causes of glycogen storage diseases (GSDs), the impact of non-glycogen-associated proteins remains underexplored. Here, our study reveals that RBCK1, a ubiquitin ligase, plays a critical role in maintaining glycogen metabolism and cardiac function. We utilized human pluripotent stem cell-derived cardiomyocytes to demonstrate that RBCK1 deficiency causes significant metabolic disturbances, including excessive polyglucosan body formation, cardiomyopathy, and calcium signaling defects. Mechanistically, we found that expression of a RBCK-binding mitochondrial protein was reduced in RBCK1-deficient cells. This reduction promoted trans-localization of a glycolytic enzyme to the cytoplasm, promoting glycogen synthesis. Furthermore, we discovered a small molecule promotes the mitochondrial glycolytic enzyme activity, redirecting glucose towards glycolysis and thereby reducing polyglucosan body accumulation. Thus, deficiency of RBCK1 results in glycogen accumulation, energy imbalance, and severe cardiac phenotypes, including dilated cardiomyopathy (DCM). These findings reveal regulatory mechanisms in glycogen metabolism beyond canonical pathways and highlight potential therapeutic targets for conditions such as cardiomyopathy associated with metabolic disorders.
