Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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.
Hif-2α promotes degradation of Mammalian peroxisomes by selective autophagy.
CELL METAB. 2014; 20(5): 882-897.
Doi: 10.1016/j.cmet.2014.09.017
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- Co-Autor*innen der Med Uni Graz
- Horn Michael
- Köfeler Harald
- Schwarz Thomas
- Trötzmüller Martin
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- 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. Copyright © 2014 Elsevier Inc. All rights reserved.