Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and prevents cystogenesis

Fibrocystin/Polyductin (FPC) is encoded by PKHD1 which, when mutated, causes autosomal recessive polycystic kidney disease (ARPKD). FPC’s function and its role in cystogenesis are unknown. We describe that endogenous FPC undergoes complex proteolytic processing, generating three small C-terminal fragments (ICDs), one of which (ICD15) contains a novel mitochondrial targeting sequence that directs its translocation into mitochondria. Pkhd1 inactivation leads to aberrant ultrastructural morphology of mitochondria in proximal tubules of developing kidneys. FPC inactivation enhances renal cystogenesis and causes severe pancreatic cystogenesis in a Pkd1 mouse mutant with blocked G protein‐coupled receptor proteolysis site (GPS) cleavage of the Pkd1-encoded Polycystin-1 protein. Deletion of the ICD15 region, encoded by exon 67, is sufficient to enhance renal cystogenesis but does not cause pancreatic cystogenesis. Our results connect FPC, a ciliary protein, directly to a mitochondrial signaling pathway whose perturbation is implicated in PKD pathogenesis.