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

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 and Feng Qian ()
Additional contact information
Rebecca V Walker: University of Maryland School of Medicine
Qin Yao: University of Maryland School of Medicine
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42196-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42196-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42196-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().