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

Author

Listed:
  • 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
    Yale University)

  • 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
    Yale University School of Medicine)

  • Weiwei Wang

    (Yale University School of Medicine)

  • Hongying Shen

    (Yale University School of Medicine
    Yale University)

  • Stefan Somlo

    (Yale University School of Medicine)

  • Michael J. Caplan

    (Yale University School of Medicine)

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.

Suggested Citation

  • 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 Sh, 2023. "The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37449-1
    DOI: 10.1038/s41467-023-37449-1
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    References listed on IDEAS

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    1. Sachin Hajarnis & Ronak Lakhia & Matanel Yheskel & Darren Williams & Mehran Sorourian & Xueqing Liu & Karam Aboudehen & Shanrong Zhang & Kara Kersjes & Ryan Galasso & Jian Li & Vivek Kaimal & Steven L, 2017. "microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    2. Xiaojian Shi & Bryn Reinstadler & Hardik Shah & Tsz-Leung To & Katie Byrne & Luanna Summer & Sarah E. Calvo & Olga Goldberger & John G. Doench & Vamsi K. Mootha & Hongying Shen, 2022. "Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Domen Kampjut & Leonid A. Sazanov, 2019. "Structure and mechanism of mitochondrial proton-translocating transhydrogenase," Nature, Nature, vol. 573(7773), pages 291-295, September.
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    Cited by:

    1. Rebecca V Walker & Qin Yao & Hangxue Xu & Anthony Maranto & Kristen F Swaney & Sreekumar Ramachandran & Rong Li & Laura Cassina & Brian M Polster & Patricia Outeda & Alessandra Boletta & Terry Watnick, 2023. "Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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