title: Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy.
abstract: Peroxisomes play a central role in lipid metabolism, and their function depends on molecular oxygen. Low oxygen tension or von Hippel-Lindau (Vhl) tumor suppressor loss is known to stabilize hypoxia-inducible factors alpha (Hif-1α and Hif-2α) to mediate adaptive responses, but it remains unknown if peroxisome homeostasis and metabolism are interconnected with Hif-α signaling. By studying liver-specific Vhl, Vhl/Hif1α, and Vhl/Hif2α knockout mice, we demonstrate a regulatory function of Hif-2α signaling on peroxisomes. Hif-2α activation augments peroxisome turnover by selective autophagy (pexophagy) and thereby changes lipid composition reminiscent of peroxisomal disorders. The autophagy receptor Nbr1 localizes to peroxisomes and is likewise degraded by Hif-2α-mediated pexophagy. Furthermore, we demonstrate that peroxisome abundance is reduced in VHL-deficient human clear cell renal cell carcinomas with high HIF-2α levels. These results establish Hif-2α as a negative regulator of peroxisome abundance and metabolism and suggest a mechanism by which cells attune peroxisomal function with oxygen availability.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland; Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Walter
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland; Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Schönenberger
authors.affiliation: Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Trötzmüller
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Horn
authors.affiliation: Department of Cytobiology, Philipps-University Marburg, D-35037 Marburg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.affiliation: Kennedy Krieger Institute, Baltimore, MD 21205, USA.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.affiliation: ScopeM - Scientific Center for Optical and Electron Microscopy, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Lucas
authors.affiliation: ScopeM - Scientific Center for Optical and Electron Microscopy, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Division of Endocrinology and Diabetes, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Gerber
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Harald C
authors.initials: HC
authors.lastname: Köfeler
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland; Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, CH-8093 Zurich, Switzerland. Electronic address: wilhelm.krek@biol.ethz.ch.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland; Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, CH-8093 Zurich, Switzerland. Electronic address: werner.kovacs@biol.ethz.ch.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Kovacs
mesh_terms: D000818:Animals; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1