Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction

Hannah Pellegrini; Elizabeth H Sharpe; Guangyi Liu; Eiko Nishiuchi; Nicholas Doerr; Kevin R Kipp; Tiffany Chin; Margaret F Schimmel; Thomas Weimbs

doi:10.1016/j.jbc.2023.105158

Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction

J Biol Chem. 2023 Sep;299(9):105158. doi: 10.1016/j.jbc.2023.105158. Epub 2023 Aug 12.

Authors

Hannah Pellegrini¹, Elizabeth H Sharpe¹, Guangyi Liu², Eiko Nishiuchi¹, Nicholas Doerr¹, Kevin R Kipp¹, Tiffany Chin¹, Margaret F Schimmel¹, Thomas Weimbs³

Affiliations

¹ Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
² Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA; Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
³ Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA. Electronic address: weimbs@ucsb.edu.

Abstract

Mutations in the gene encoding polycystin-1 (PC1) are the most common cause of autosomal dominant polycystic kidney disease (ADPKD). Cysts in ADPKD exhibit a Warburg-like metabolism characterized by dysfunctional mitochondria and aerobic glycolysis. PC1 is an integral membrane protein with a large extracellular domain, a short C-terminal cytoplasmic tail and shares structural and functional similarities with G protein-coupled receptors. Its exact function remains unclear. The C-terminal cytoplasmic tail of PC1 undergoes proteolytic cleavage, generating soluble fragments that are overexpressed in ADPKD kidneys. The regulation, localization, and function of these fragments is poorly understood. Here, we show that a ∼30 kDa cleavage fragment (PC1-p30), comprising the entire C-terminal tail, undergoes rapid proteasomal degradation by a mechanism involving the von Hippel-Lindau tumor suppressor protein. PC1-p30 is stabilized by reactive oxygen species, and the subcellular localization is regulated by reactive oxygen species in a dose-dependent manner. We found that a second, ∼15 kDa fragment (PC1-p15), is generated by caspase cleavage at a conserved site (Asp-4195) on the PC1 C-terminal tail. PC1-p15 is not subject to degradation and constitutively localizes to the mitochondrial matrix. Both cleavage fragments induce mitochondrial fragmentation, and PC1-p15 expression causes impaired fatty acid oxidation and increased lactate production, indicative of a Warburg-like phenotype. Endogenous PC1 tail fragments accumulate in renal cyst-lining cells in a mouse model of PKD. Collectively, these results identify novel mechanisms regarding the regulation and function of PC1 and suggest that C-terminal PC1 fragments may be involved in the mitochondrial and metabolic abnormalities observed in ADPKD.

Keywords: ADPKD; PC1; ROS; metabolism; mitochondria; oxidative stress; polycystic kidney disease; polycystin-1.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Mice
Mitochondrial Diseases*
Oxidative Stress
Polycystic Kidney, Autosomal Dominant* / metabolism
Reactive Oxygen Species / metabolism
TRPP Cation Channels* / genetics
TRPP Cation Channels* / metabolism

Substances

Reactive Oxygen Species
TRPP Cation Channels
polycystic kidney disease 1 protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding