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.
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic cause of kidney failure, marked by fluid-filled cysts, aberrant cell proliferation, metabolic reprogramming, and extensive genetic and epigenetic alterations. The mechanisms by which loss-of-function mutations in PKD1 and PKD2 drive disease progression remain poorly understood. Here, we demonstrate that ER-mitochondria contacts are disrupted in Pkd -mutant mice prior to cyst formation. This disconnection induces mitochondrial dysfunction and epigenetic remodeling, which in turn promote metabolic reprogramming and cystogenesis. Restoration of PKD function in the ER or pharmacological enhancement of ER-mitochondria coupling mitigates these pathological changes. Our findings uncover a critical role for ER-mitochondria crosstalk in suppressing cystogenesis and identify a promising therapeutic target for ADPKD.
