Endoplasmic reticulum-mitochondrion disconnection promotes metabolic reprogramming and cystogenesis in polycystic kidney disease

Mutations in PKD1 and PKD2 cause autosomal-dominant polycystic kidney disease (ADPKD), characterized by fluid-filled cysts, aberrant cell proliferation, and widespread genetic and epigenetic remodeling. While mitochondrial dysfunction and metabolic shifts are central to disease progression, the mechanisms linking PKD mutations to these changes remain unclear. Here, we demonstrate that ER-mitochondria connectivity was disrupted in Pkd1- and Pkd2- deleted mice, preceding cyst formation. This disconnection induces mitochondrial stress, triggering epigenetic remodeling and transcriptional activation of pathways driving proliferation and metabolic reprogramming. Remarkably, restoring PKD function in the ER or pharmacologically enhancing ER-mitochondria connection ameliorates mitochondrial dysfunction, epigenetic shifts, and cystogenesis. These findings reveal a critical role for ER-localized PKD in maintaining mitochondrial integrity and transcriptional homeostasis. Mitochondrial dysfunction resulting from ER-mitochondria uncoupling emerges as a key driver of cystogenesis in ADPKD, and correcting this defect may offer a promising therapeutic strategy.