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Mol Biol Cell. 2017 Jan 15;28(2):261-269. doi: 10.1091/mbc.E16-08-0597. Epub 2016 Nov 23.

The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function.

Author information

  • 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
  • 2Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
  • 3Systems Biology Institute, Yale University, West Haven, CT 06516.
  • 4Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
  • 5Division of Genetics and Cell Biology, Dibit, San Raffaele Scientific Institute, 20132 Milan, Italy.
  • 6Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520 michael.caplan@yale.edu.

Abstract

Autosomal dominant polycystic kidney disease is caused by mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which form an ion channel complex that may mediate ciliary sensory processes and regulate endoplasmic reticulum (ER) Ca2+ release. Loss of PC1 expression profoundly alters cellular energy metabolism. The mechanisms that control the trafficking of PC1 and PC2, as well as their broader physiological roles, are poorly understood. We found that O2 levels regulate the subcellular localization and channel activity of the polycystin complex through its interaction with the O2-sensing prolyl hydroxylase domain containing protein EGLN3 (or PHD3), which hydroxylates PC1. Moreover, cells lacking PC1 expression use less O2 and show less mitochondrial Ca2+ uptake in response to bradykinin-induced ER Ca2+ release, indicating that PC1 can modulate mitochondrial function. These data suggest a novel role for the polycystins in sensing and responding to cellular O2 levels.

PMID:
27881662
PMCID:
PMC5231895
[Available on 2017-03-30]
DOI:
10.1091/mbc.E16-08-0597
[PubMed - in process]
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