RRC ID 32240
Author Walter KM, Schönenberger MJ, Trötzmüller M, Horn M, Elsässer HP, Moser AB, Lucas MS, Schwarz T, Gerber PA, Faust PL, Moch H, Köfeler HC, Krek W, Kovacs WJ.
Title Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy.
Journal Cell Metab
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.
Volume 20(5)
Pages 882-897
Published 2014-11-4
DOI 10.1016/j.cmet.2014.09.017
PII S1550-4131(14)00440-9
PMID 25440060
MeSH Animals Autophagy* Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / metabolism Cell Line, Tumor Gene Deletion Gene Expression Regulation, Neoplastic Humans Kidney / metabolism Kidney Neoplasms / genetics Kidney Neoplasms / metabolism Mice Mice, Knockout Peroxisomes / genetics Peroxisomes / metabolism* Von Hippel-Lindau Tumor Suppressor Protein / genetics Von Hippel-Lindau Tumor Suppressor Protein / metabolism
IF 21.567
Times Cited 65
Mice RBRC02759