Hif-2α Promotes Degradation of Mammalian Peroxisomes by Selective Autophagy

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-1 alpha and Hif-2 alpha) to mediate adaptive responses, but it remains unknown if peroxisome homeostasis and metabolism are interconnected with Hif-a signaling. By studying liver-specific Vhl, Vhl/Hif1 alpha, and Vhl/Hif2 alpha knockout mice, we demonstrate a regulatory function of Hif-2 alpha signaling on peroxisomes. Hif-2 alpha 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-2 alpha-mediated pexophagy. Furthermore, we demonstrate that peroxisome abundance is reduced in VHL-deficient human clear cell renal cell carcinomas with high HIF-2 alpha levels. These results establish Hif-2 alpha as a negative regulator of peroxisome abundance and metabolism and suggest a mechanism by which cells attune peroxisomal function with oxygen availability.