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

Abstract

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.

DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2

“…Interestingly, our cell-based assays showed that disruption of DLG1 leads to over-activation of TAK1 in line with a recent study, showing that Dlg1 deficiency in mouse microglial cells impairs microglial activation and prevents production of inflammatory cytokines [83]. Furthermore, multiple lines of evidence have shown that alterations in ciliary length and inactivation of polycystins can cause profound metabolic rewiring in the kidney, which likely contributes to development of PKD [84][85][86]. Nevertheless, if and how altered ciliary length and composition, as well as dysregulated metabolic, NFκB and TGFβ signalling, contribute to the kidney defects observed in Dlg1 deficient mice and human CAKUT patients with DLG1 mutations awaits further investigation.…”

Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease

“…While our studies provide novel information about the nuclear trafficking and function of human and mouse FPC-CTDs, a recent study identified mitochondrial targeting sequences in both mFPC-CTD and hFPC-CTD and demonstrated the trafficking of these proteins into the mitochondria ( Walker et al, 2022 ). These developments imply that understanding both the nuclear and mitochondrial functions of human and mouse FPC-CTDs will be necessary to better define their roles in kidney cystogenesis.…”

The molecular structure and function of fibrocystin, the key gene product implicated in autosomal recessive polycystic kidney disease (ARPKD)

“…Gene‐edited cultured HEK‐293 cells carrying clinically relevant PKHD1 truncating variants displayed aberrant mitochondrial morphology and increased oxygen consumption and extracellular acidification rates (Chumley et al., 2019). A very recent study identified a shorter ICD fragment (ICD 15 ) that localises to mitochondria via a cryptic mitochondrial targeting sequence (MTS) that overlaps partially with the NLS (Walker et al., 2023). Electron microscopy on renal tubule cells in kidneys from Pkhd1 KO mice revealed mitochondria with significantly decreased surface area, increased roundness and swollen cristae, suggesting a change to the inner mitochondrial membrane.…”

“…Electron microscopy on renal tubule cells in kidneys from Pkhd1 KO mice revealed mitochondria with significantly decreased surface area, increased roundness and swollen cristae, suggesting a change to the inner mitochondrial membrane. Although mice homozygous for Pkhd1 exon 67 deletion appear healthy (Outeda et al., 2017), this deletion (which removes the MTS) enhanced renal cystogenesis in a Pkd1 ‐defective background (Walker et al., 2023). The FC C‐terminal domain may thus play complex roles in both the nucleus and the mitochondria.…”