RhoA through its various effectors mediate mitochondrial fragmentation in polycystic kidney disease.

Polycystic kidney disease (PKD), the most common genetic nephropathy, is caused by the loss/loss of function of polycystin-1 (PC1) or 2 (PC2) and characterized by cyst formation and fibrosis. A key feature of PKD is mitochondrial fragmentation, but the underlying mechanism is unknown. Since PC1/PC2 loss induces RhoA activation and fibrogenesis, we hypothesized that RhoA might also trigger general and/or PC1/2 loss-induced mitochondrial fragmentation. We show that RhoA activation is sufficient to induce DRP1-mediated mitochondrial fission in tubular cells. Importantly, genetic or pharmacologic inhibition of RhoA or its effectors (ROCK/LIM kinase/cofilin, phospho-myosin or formins) prevents/reverses PC1/PC2 loss-provoked fragmentation. Fragmentation by active formins requires F-actin polymerizing capacity but not binding to INF2, a RhoA-independent, fission-mediating formin. PC1 re-expression or RhoA/RhoA effector inhibition restores mitochondrial morphology in human PKD cells. Mitochondrial fragmentation facilitates fibrogenesis. Thus, RhoA regulates mitochondrial shape, and RhoA-mediated actin polymerization/myosin activation is a central mechanism of PKD-associated mitochondrial fragmentation.