The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 30, 2023
- Source ID
- 10.1038/s41467-023-37449-1
Entities
People
- Giorgia Schena
- Hongying Shen
- Ke Dong
- Laura Onuchic
- Michael J Caplan
- Nikolay P. Gresko
- Omair Ahmed
- Raj Pandya
- Stefan Somlo
- TuKiet T Lam
- Valeria Padovano
- Vanathy Rajendran
- Victoria Rai
- Weiwei Wang
- Xiaojian Shi
Organizations
- Congressionally Directed Medical Research Programs
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of General Medical Sciences
- Polycystic Kidney Disease Foundation
- United States Department of Defense
- United States Department of Health and Human Services