Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD₁₅, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1^V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD₁₅ enhances renal cystogenesis without inducing pancreatic cysts in Pkd1^V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD₁₅ cleavage, crucial for cystogenesis mechanisms.

由PKHD1编码的纤维囊蛋白/多导蛋白 (FPC) 与常染色体隐性多囊肾病 (ARPKD) 相关，但其在囊肿发生中的确切作用仍不清楚。在这里，我们展示了 FPC 在发育中的肾脏中经历复杂的蛋白水解过程，产生三个可溶性 C 末端片段 (ICD)。值得注意的是，ICD ₁₅在其 N 末端含有一个新的线粒体靶向序列，有助于其易位到线粒体中。这增强了肾上皮细胞中的线粒体呼吸，部分恢复了因 FPC 丢失而受损的线粒体功能。 FPC 失活导致肾小管线粒体超微结构形态异常，但不形成囊肿。此外，FPC 失活显着加剧肾囊肿发生，并在Pkd1小鼠突变体Pkd1 ^V/V中引发严重的胰腺囊肿发生，其中Pkd1编码的 Polycystin-1 在 GPCR 蛋白水解位点的裂解被阻断。删除 ICD ₁₅可增强Pkd1 ^V/V小鼠的肾囊肿发生，而不诱导胰腺囊肿。这些发现揭示了 FPC 与通过 ICD ₁₅裂解的线粒体途径之间的直接联系，这对于囊肿发生机制至关重要。