title: The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function.
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 O2levels 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 O2and 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 O2levels.
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Valeria
authors.initials: V
authors.lastname: Padovano
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Ivana Y
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Stavola
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.|Systems Biology Institute, Yale University, West Haven, CT 06516.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Aerni
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Flaherty
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Chapin
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Ming
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.affiliation: Division of Genetics and Cell Biology, Dibit, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boletta
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Ehrlich
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.|Systems Biology Institute, Yale University, West Haven, CT 06516.
authors.forename: Jesse
authors.initials: J
authors.lastname: Rinehart
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520 michael.caplan@yale.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism / Q000502:physiology; D018374:LLC-PK1 Cells; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D013552:Swine; D050396:TRPP Cation Channels / Q000378:metabolism* / Q000502:physiology*
chemical_list: D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen; D050396:TRPP Cation Channels; C488894:EGLN3 protein, human