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

Katharina M. Walter, Miriam J. Schönenberger, Martin Trötzmüller, Michael Horn, Hans Peter Elsässer, Ann B. Moser, Miriam S. Lucas, Tobias Schwarz, Philipp A. Gerber, Phyllis L. Faust, Holger Moch, Harald C. Köfeler, Wilhelm Krek, Werner J. Kovacs

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)882-897
Number of pages16
JournalCell Metabolism
Volume20
Issue number5
DOIs
StatePublished - Nov 4 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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