Kidney Week

Abstract: FR-PO281

Cleavage of Pkhd1 Results in a Small Fragment That Localizes and Functions Within Mitochondria

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Walker, Rebecca V., University of Maryland Baltimore, Baltimore, Maryland, United States

Rebecca V. Walker,

• Maranto, Anthony R., University of Maryland Baltimore, Baltimore, Maryland, United States

Anthony R. Maranto,

• Outeda, Patricia, University of Maryland Baltimore, Baltimore, Maryland, United States

Patricia Outeda,

• Xu, Hangxue, University of Maryland Baltimore, Baltimore, Maryland, United States

Hangxue Xu,

• Watnick, Terry J., University of Maryland Baltimore, Baltimore, Maryland, United States

Terry J. Watnick,

• Qian, Feng, University of Maryland Baltimore, Baltimore, Maryland, United States

Feng Qian,

Group or Team Name

• Qian lab

Background

Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1 encoding FPC, and is characterized by severe renal cystogenesis in neonates, yet mouse models do not fully recapitulate the human phenotype.

Methods

We use mouse models, biochemistry, cell models, and proteomics to reveal novel cleavage fragments of FPC and their effect on enhancing cystogenesis in Pkd1 mutant cyst-sensitized mice.

Results

We describe how Pkhd1 mutation modifies a Pkd1 uncleavable mutant (Pkd1^V), enhancing the cystic phenotype in kidney and pancreas, and revealing some elusive functions of FPC. FPC displays differential cleavage to produce fragments of unknown function. We identify several of these cleavage fragments and describe the mitochondrial localization of one small C-terminal fragment, induced by a newly identified mitochondria localizing signal presented in the fragments. Mitochondrial proteomics revealed that mice lacking FPC have significant changes compared to Wt. Finally, we show that deletion of just the C-terminal fragment of FPC (ΔCT) is sufficient to enhance the renal cystic phenotype of the PC1 cleavage mutant but does not result in the pancreatic cystogenesis seen in other Pkhd1 mutants on this background.

Conclusion

Our results suggest that the C-terminus of FPC plays an important role in preventing cystogenesis via a novel mitochondria specific function.

Funding

• NIDDK Support