ATG7 Drives Metabolic Cell-Fate Decisions in Kidney Tubule Homeostasis and Disease

Background: Specialized epithelial cells must coordinate metabolic pathways with differentiation cues to fulfil their functions and maintain homeostasis. A paradigm for this concept is provided by proximal tubule (PT) cells in the kidney, which require high energy to recover ultrafiltered proteins and solutes via endocytosis and lysosomal degradation. Simultaneously, autophagy recycles intracellular components to support energy metabolism and homeostasis. Central to autophagy biogenesis is ATG7 — a conserved E1-like enzyme that conjugates ATG12 to ATG5 and lipidates MAP1LC3-I into MAP1LC3-II, a bona fide biosensor of autophagy levels in cells and tissues. While ATG7-dependent autophagy is recognized for its role in resilience in response to cellular stressors, its basal function in shaping the metabolic PT cell-fate specialization remains poorly understood. Methods: We integrated genetically engineered models (mouse, C. elegans, and zebrafish) with physiologically relevant PT cell cultures, functional lipid metabolism assays (e.g., pulse-chase using fluorescent lipid droplet and fatty acid probes), multi-omics analyses, and human genetics to investigate the role of ATG7 in PT cell-fate decisions and determination. Results: In mice, PT-specific deletion of ATG7 forces differentiated cells into anabolic, proliferative states, leading to the appearance in the urine of essential nutrients and causing proximal tubulopathy. Mechanistically, loss of ATG7 impairs the clearance of lipid droplets, restricts fatty-acid (FA) metabolism, and depletes cellular energy required for transport and reabsorptive functions. In zebrafish pronephros, re-expression of wild-type ATG7 rescues reabsorption in atg7 mutants, whereas inhibiting FA oxidation triggers dysfunction. In humans, ATG7 variants associate with cardio-renal-metabolic health and increased kidney disease risk, whereas low ATG7 levels predict poor survival in clear cell renal carcinoma. Conclusion: Taken together, these findings establish a conserved paradigm coupling ATG7/autophagy and lipid energy metabolism to epithelial cell-fate specialization in the kidney tubule, thus carrying implications for health, disease, and therapeutic discovery.