WEHI Ubiquitin Signalling Centre special seminar hosted by Professor David Komander

Dr Meagan McGrath

Group Leader – Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute – Monash University

Lysosome recycling is essential in skeletal muscle for health and glycogen metabolism

This is an in-person presentation

Davis Auditorium

Including Q&A session

Please note this presentation will not be recorded

Lysosomes are the central catabolic organelle within cells. In recent times knowledge of their role has radically shifted from mere ‘garbage disposal’ to a hub for coordinating nutrient processing with energy surveillance, including glucose sensing. How lysosome formation shapes systemic metabolism remains unknown. We show that autophagic membranes, which are abundantly generated during fasting, are recycled to regenerate lysosomes via autophagic lysosome reformation (ALR). We show that this process is essential to maintain lysosomal function and metabolic capacity in skeletal muscles challenging the view that lysosomes are primarily synthesized de novo. Strikingly, ablation of ALR in muscle confers profound resistance to age- and diet-induced obesity and hepatic steatosis independently of canonical metabolic pathways, food intake, or energy expenditure. Instead, lysosomal breakdown of glycogen is blocked due to failed maturation of acid α-glucosidase (GAA). The canonical glycogen metabolism pathway that operates in the cytosol (glycogenolysis) fails to compensate for this defect, resulting in impaired glycogen utilization during fasting and exercise. In turn this triggers a metabolic shift toward enhanced fat metabolism in muscle, driving marked resistance to obesity and with near complete protection from hepatosteatosis. Together, these findings establish autophagy-driven lysosomal regeneration as a novel metabolic rheostat driving glycogen metabolism and systemic metabolic flexibility.
 

All Welcome!