Taken together, our findings (1) reveal a common cellular phenotype for mutations mapping to the leader peptide or pro-sequence of renin that share common disease features; (2) suggest that localisation of the renin pre-pro-peptide to mitochondria, whether it is induced by an ADTKD-related mutation or by interfering with ER entry, leads to a mitochondrial phenotype; and (3) provide new insight into the molecular pathogenesis of the disease. This evidence concerns the gene REN and autosomal dominant medullary cystic kidney disease with or without hyperuricemia.