Invited Speaker 11th International Symposium on Autophagy 2025

Autophagy-driven lysosome recycling is essential for glycogen metabolism in skeletal muscle (129777)

Meagan McGrath 1 , Kai Qin Le 2 , Rajendra Gurung 2 , Matthew J. Eramo 2 , Stephen Cui 2 , Chrysovalantou E. Xirouchaki 1 , Joel Eliades 3 , Stephanie Simonds 4 , Yuqin Wu 1 , Helen Stölting 1 , Sonia R. Lourdes 2 , Saveen Giri 2 , Rachel Templin 5 , Georg Ramm 5 6 , Catriona A. McLean 7 , Tsuyoshi Morita 8 , Otto Baba 8 , Elizabeth M. Davies 2 , Juan Nunez-Iglesias 9 , Adam J. Rose 1 , Michael A. Cowley 4 , Tony Tiganis 1 , Christina A. Mitchell 2
  1. Department of Biochemistry and Molecular Biology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  3. Metabolic Phenotyping Platform, Monash University, Melbourne, Victoria, Australia
  4. Department of Physiology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  5. Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, VIC, Australia
  6. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  7. Department of Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia
  8. Oral and Maxillofacial Anatomy, Tokushima University Graduate School, Tokushima, Japan
  9. Monash eResearch Centre, Monash University, Melbourne, VIC, Australia

The ability to adapt to dietary variation is critical for survival. Lysosomes are integral to nutrient sensing and processing, yet their role in metabolism remains unclear. We report a new paradigm for metabolic regulation via autophagy, that transforms fundamental knowledge on the relationship between lysosome plasticity and metabolic flexibility. We show that autolysosomes, rather than serving as passive endpoints of fasting-induced autophagy in skeletal muscle, are instead metabolically reprogrammed via membrane recycling to produce lysosomes for glycogen metabolism (glycophagy). Called autophagic lysosome reformation (ALR), we show that lysosomes generated via this route are utilised for maturation and activity of the sole glycophagy enzyme acid alpha-glucosidase. We further identify that this process is governed by a nutrient-responsive phosphoinositide switch on autolysosomal membranes, via the interconvertsion of PtdIns4P and PtdIns(4,5)P2. Disruption of this phosphoinositide switch in Inpp5k-deficient muscle uncouples glycogen metabolism from fasting and exercise. Consequently, systemic metabolic flexibility is reprogrammed from glycogen to fat metabolism during nutrient scarcity, with striking effects on resistance to obesity and hepatosteatosis. These systemic effects were also unexpectedly independent of well-known autophagy metabolic adaptions that result in leanness including appetite suppression and FGF21-mediated thermogenesis. In proof of concept, reconstitution of PtdIns(4,5)P2 to PtdIns4P conversion on autolysosomes restores ALR, lysosome function, glycophagy and glycogen metabolism. Therefore, ALR in muscle couples membrane recycling to adaptive fasting metabolism, as an indispensable route for optimal glycogen metabolism.