Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1 ). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1 mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1 mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.