Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy - PubMed (original) (raw)

. 2014 Nov 4;20(5):882-897.

doi: 10.1016/j.cmet.2014.09.017. Epub 2014 Nov 4.

Miriam J Schönenberger 1, Martin Trötzmüller 2, Michael Horn 3, Hans-Peter Elsässer 4, Ann B Moser 5, Miriam S Lucas 6, Tobias Schwarz 6, Philipp A Gerber 7, Phyllis L Faust 8, Holger Moch 9, Harald C Köfeler 2, Wilhelm Krek 10, Werner J Kovacs 11

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

Katharina M Walter et al. Cell Metab. 2014.

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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.

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