Fig. 7: Model of FPC and Polycystin-1 interaction in the pathogenesis of polycystic kidney disease via a cilia-mitochondria connection.

a In WT kidney, the ciliary component of the cilia-dependent cyst activation (CDCA) signal is repressed by ciliary Polycystins, cellular Polycystins, and ciliary FPC. FPC cleavage produces ICD₁₅. ICD₁₅ translocates to mitochondria and produces ICD₁₂, which inhibits the propagation of the CDCA signal. The C-terminal tail (CTT) of PC1 may also enter mitochondria and inhibit the propagation of CDCA. These factors lead to the regulation of normal tubule diameter. b In Pkd1^V/V kidney, PC1^V exhibits impaired localization to the cilia^22,23. The CDCA is activated but its activity is suppressed by PC1^V in the cell body and by both its CTT and ICD₁₅ in mitochondria, leading to modest cystogenesis. c In ΔCT/V (Pkhd1^Δ67/Δ67;Pkd1^V/V) kidney, in addition to the activation of CDCA by loss of ciliary PC1, ICD₁₅ and ICD₁₂ cannot be produced and cannot inhibit the propagation of the CDCA signal, resulting in enhanced cystogenesis compared with Pkd1^V/V single mutants. However, FPC-ΔCT is still able to localize to the cilium and reduce CDCA. d In KO/V (Pkhd1^-/-;Pkd1^V/V) kidney, the only remaining inhibition to the CDCA comes from extra-ciliary PC1^V and possibly its CTT in mitochondria; thus cystogenesis is severe. e Summary of the model. FPC and PC1 work together to prevent the initiation and propagation of the cystogenic signal generated in cilia. Figure created in BioRender.