Autophagy regulator ATG7 links energy metabolism to tubular cell fate specialization and kidney disease

Precise coupling between differentiation and metabolism in the kidney proximal tubule (PT) is critical for homeostasis, yet determinants of tubular cell fate specialization remain unclear. Using genetically engineered model organisms, cell cultures, proteomic and metabolomic profiling, and human genetics, we show that ATG7 deficiency shifts PT cell metabolism and differentiation toward growth at the expense of function. ATG7 loss impairs autophagy-mediated lipid droplet homeostasis, causing their accumulation and disrupting fatty acid transfer to mitochondria, compromising energy metabolism and cellular function. In zebrafish, reintroducing human wild-type ATG7 restores homeostasis, whereas inhibiting mitochondrial fatty acid oxidation induces phenotypic changes in wild-type cells. In humans, ATG7 variation associates with increased kidney disease risk, and loss-of-function variants cause tubular proteinuria and altered mitochondrial metabolism. Low ATG7 levels correlate with dedifferentiation, altered metabolic pathways, and poor renal cell carcinoma outcomes. Together, our results establish a metabolic paradigm that links autophagy to kidney epithelial cell fate specialization, with broad implications for health and disease.