A Personalized Model of Nephropathy Rescued by the Wild-Type Allele or Dietary Coenzyme Q Supplementation.

Clinical studies have identified patients with nephrotic syndrome caused by mutations in genes involved in the biosynthesis of coenzyme Q (CoQ), a lipid component of the mitochondrial electron transport chain and an important antioxidant. However, the cellular mechanisms through which these mutations induce podocyte injury remain obscure. Here, we exploited the striking similarities between nephrocytes and human podocytes to develop a model of these renal diseases, and performed a systematic analysis assessing the role of CoQ pathway genes in renal function. Nephrocyte-specific silencing of , , and , which are genes involved in the CoQ pathway that have been associated with genetic nephrotic syndrome in humans, induced dramatic adverse changes in these cells. In particular, silencing of led to an abnormal localization of slit diaphragms, collapse of lacunar channels, and more dysmorphic mitochondria. In addition, -deficient nephrocytes showed elevated levels of autophagy and mitophagy, increased levels of reactive oxygen species, and increased sensitivity to oxidative stress. Dietary supplementation with CoQ at least partially rescued these defects. Furthermore, expressing the wild-type human gene specifically in nephrocytes rescued the defective protein uptake, but expressing the mutant allele derived from a patient with nephropathy did not. We conclude that transgenic lines carrying mutations in the CoQ pathway genes are clinically relevant models with which to explore the pathogenesis of podocyte injury and could serve as a new platform to test novel therapeutic approaches.