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Cell Metab. 2014 Nov 4;20(5):882-897. doi: 10.1016/j.cmet.2014.09.017. Epub 2014 Nov 4.

Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy.

Author information

1
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.
2
Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, A-8010 Graz, Austria.
3
Institute of Molecular Health Sciences, ETH Zurich, CH-8093 Zurich, Switzerland.
4
Department of Cytobiology, Philipps-University Marburg, D-35037 Marburg, Germany.
5
Kennedy Krieger Institute, Baltimore, MD 21205, USA.
6
ScopeM - Scientific Center for Optical and Electron Microscopy, ETH Zurich, CH-8093 Zurich, Switzerland.
7
Division of Endocrinology and Diabetes, University Hospital Zurich, CH-8091 Zurich, Switzerland.
8
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
9
Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
10
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.
11
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.

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.

PMID:
25440060
DOI:
10.1016/j.cmet.2014.09.017
[Indexed for MEDLINE]
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