Journal Article

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

Lam, TuKiet T., Onuchic, Laura, Pandya, Raj, Ahmed, Omair, Rajendran, Vanathy, Dong, Ke, Somlo, Stefan, Rai, Victoria, Schena, Giorgia, Caplan, Michael J., Shen, Hongying, Wang, Weiwei, Shi, Xiaojian, Gresko, Nikolay P., Padovano, Valeria

2023

Overview

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid (aa) residues of PC1 in two Pkd1 -KO orthologous murine models of ADPKD suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function, and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD. Mutations in the gene encoding PC1 cause ADPKD, a common genetic renal disease. Here, the authors show that expression of the C-terminal 200 amino acids of the large PC1 protein in mouse models of ADPKD suppresses cystic disease through an interaction with the mitochondrial enzyme NNT.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 14/19 / 38/77 / 42/70 / 631/443/272 / 64/60 / 692/4022 / 692/4022/1585/1589 / 82/1 / 82/58 / Amino acids / Animal models / Animals / Cell proliferation / Cleavage / Disease Models, Animal / Enzymes / Gene therapy / Humanities and Social Sciences / Humans / Kidney - pathology / Kidney - physiology / Kidney diseases / Mice / Mitochondria / Mitochondrial Proteins - metabolism / multidisciplinary / Mutation / NADP Transhydrogenase, AB-Specific - metabolism / Nicotinamide / Nucleotides / Phenotypes / Polycystic kidney / Polycystic kidney disease 1 protein / Polycystic Kidney, Autosomal Dominant - genetics / Polycystic Kidney, Autosomal Dominant - pathology / Polycystic Kidney, Autosomal Dominant - therapy / Proteins / Redox properties / Renal function / Science / Science (multidisciplinary) / TRPP Cation Channels - genetics / TRPP Cation Channels - metabolism