Misrouting to mitochondria of renin carrying dominant mutations in the leader peptide or pro-segment.

Autosomal Dominant Tubulointerstitial Kidney Disease, a rare genetic disorder characterised by progressive chronic kidney disease, is caused by mutations in different genes including REN, encoding renin. Renin is a secreted protease composed of 3 domains: the leader peptide allowing insertion in the endoplasmic reticulum (ER), a pro-segment regulating its activity, and the mature part. Mutations in mature renin lead to ER retention of mutant protein and to late onset disease, while mutations in the leader peptide, associated with defective ER translocation, and mutations in the pro-segment, accumulating in the ER-to-Golgi compartment, lead to a more severe, early-onset disease. In this study we demonstrate a common, unprecedented effect of mutations in the leader peptide and pro-segment as they lead to full or partial mistargeting of mutated protein to mitochondria. The mutated pre-pro sequence of renin is necessary and sufficient to drive mitochondrial rerouting, mitochondrial import defect and fragmentation. Mitochondrial localisation and fragmentation are also observed for wild type renin when affecting ER translocation. These results expand the spectrum of cellular phenotypes associated with ADTKD-REN mutations providing new insight into the disease molecular pathogenesis.