PR001409 (Project)

Description:For survival, autophagy is a crucial intracellular self-degradation process to provide energy sources, helping adapt to nutrient deprivation. Although nutrient availability is a key determinant of autophagy initiation, it remains elusive underlying mechanism(s) of perceiving nutritional scarcity by which cells timely turn on autophagy as the last self-destructive process for energy supply. Here, we showed that PKA-dependent lipolysis can block the initiation of futile autophagy during short-term nutritional deprivation by repressing AMPK. Using Raman microscopy imaging and metabolomics, we found that autophagy occurred by reduction in available free fatty acids (FFAs) for energy sources. By modulating genes involved in lipolysis and fatty acid oxidation, we found that the use of lipolysis-derived FFAs precedes autophagy initiation. The dysregulated autophagy suppression during short-term fasting decreased motility and lifespan extension of worms. Taken together, these data suggest that PKA is a pivotal factor to orchestrate sophisticated catabolic pathways, preferring the use of PKA-mediated lipolytic products to repress futile autophagic degradation during short-term fasting through AMPK inhibition.