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

Laura Onuchic, Valeria Padovano, Giorgia Schena, Vanathy Rajendran, Ke Dong, Xiaojian Shi, Raj Pandya, Victoria Rai, Nikolay P. Gresko, Omair Ahmed, TuKiet T. Lam, Weiwei Wang, Hongying Shen, Stefan Somlo and Michael J. Caplan ()
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Laura Onuchic: Yale University School of Medicine
Valeria Padovano: Yale University School of Medicine
Giorgia Schena: Yale University School of Medicine
Vanathy Rajendran: Yale University School of Medicine
Ke Dong: Yale University School of Medicine
Xiaojian Shi: Yale University School of Medicine
Raj Pandya: Yale University School of Medicine
Victoria Rai: Yale University School of Medicine
Nikolay P. Gresko: Yale University School of Medicine
Omair Ahmed: Yale University School of Medicine
TuKiet T. Lam: Yale University
Weiwei Wang: Yale University School of Medicine
Hongying Shen: Yale University School of Medicine
Stefan Somlo: Yale University School of Medicine
Michael J. Caplan: Yale University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37449-1

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