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Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis

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Listed:
  • Rebecca V Walker

    (University of Maryland School of Medicine)

  • Qin Yao

    (University of Maryland School of Medicine
    National Institutes of Health)

  • Hangxue Xu

    (University of Maryland School of Medicine)

  • Anthony Maranto

    (University of Maryland School of Medicine)

  • Kristen F Swaney

    (Johns Hopkins University School of Medicine)

  • Sreekumar Ramachandran

    (Johns Hopkins University School of Medicine)

  • Rong Li

    (Johns Hopkins University School of Medicine
    Mechanobiology Institute and Department of Biological Sciences, National University of Singapore)

  • Laura Cassina

    (IRCCS San Raffaele Scientific Institute)

  • Brian M Polster

    (University of Maryland School of Medicine)

  • Patricia Outeda

    (University of Maryland School of Medicine)

  • Alessandra Boletta

    (IRCCS San Raffaele Scientific Institute)

  • Terry Watnick

    (University of Maryland School of Medicine)

  • Feng Qian

    (University of Maryland School of Medicine)

Abstract

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42196-4
    DOI: 10.1038/s41467-023-42196-4
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    1. 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.
    2. Monika Pema & Luca Drusian & Marco Chiaravalli & Maddalena Castelli & Qin Yao & Sara Ricciardi & Stefan Somlo & Feng Qian & Stefano Biffo & Alessandra Boletta, 2016. "mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    3. 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.
    4. Linhao Ruan & Chuankai Zhou & Erli Jin & Andrei Kucharavy & Ying Zhang & Zhihui Wen & Laurence Florens & Rong Li, 2017. "Cytosolic proteostasis through importing of misfolded proteins into mitochondria," Nature, Nature, vol. 543(7645), pages 443-446, March.
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