In summary, by generating a mouse model that resembles ADTKD-UMOD carrying a prevalent human mutation, and by employing both loss- and gain-of-function studies of MANF, our work has discovered that MANF is an important regulator of autophagy/mitophagy and mitochondrial homeostasis in mutant TALs through activation of p-AMPK in ADTKD-UMOD, thereby mitigating cGAS/STING activation and promoting autophagic degradation of mutant UMOD (Fig. 9). This evidence concerns the gene MANF and autosomal dominant medullary cystic kidney disease with or without hyperuricemia.