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

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.

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

“…51,52 Previous studies have shown that HIF1A contributes to autophagy regulation in hypoxia. 20,[24][25][26][27][68][69][70] The BH3 domains of BNIP3 and BNIP3L, known HIF1A targets, disrupt the BCL2-BECN1 complex, releasing more BECN1 to be involved in the autophagic process. 24 In NP cells, although the BNIP3 level was increased under hypoxia, the absence of a concomitant increase in p-BECN1 Ser93 indicated a possible lack of correlation with autophagic induction.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…HIF-1α activation as a result of VHL loss or pseudohypoxia contributes also to the development of the Warburg effect. Furthermore, although the shift from oxidative phosphorylation to glycolysis is attributed to the activity of HIF-1α, at least in the liver HIF-2α induces the same genes involved in this metabolic adaptation (Rankin et al, 2009;Walter et al, 2014).…”

“…Mitochondrial protein levels are similar in control and knockout livers (Walter et al, 2014), suggesting that constitutive HIF-α signaling does not affect hepatic mitochondrial mass. However, subcellular fractionation of livers from control and Vhl −/− mice shows that mitochondrial protein levels are decreased in the heavy mitochondrial fraction of Vhl −/− livers compared with controls, whereas their levels are increased in the light mitochondrial fraction (Walter et al, 2014). Further purification of the light mitochondrial fraction by density gradient centrifugation and immunoblots of gradient fractions show that the OMM protein VDAC shifts toward lower density fractions.…”

“…Their overexpression increases peroxisome number in the absence of extracellular stimuli or peroxisome metabolism (Li and Gould, 2002;. Recently, we showed that activation of HIF-α signaling in the liver does not affect the expression of Pex genes (Walter et al, 2014). Pex11α is the only peroxin that is transcriptionally induced in response to HIF-2α activation in Vhl −/− and Vhl −/− /Hif1α −/− livers (Walter et al, 2014).…”

“…Recently, we showed that activation of HIF-α signaling in the liver does not affect the expression of Pex genes (Walter et al, 2014). Pex11α is the only peroxin that is transcriptionally induced in response to HIF-2α activation in Vhl −/− and Vhl −/− /Hif1α −/− livers (Walter et al, 2014). The peroxisome biogenesis machinery in Vhl −/− livers is functional, because peroxisome proliferation can be induced by treatment with PPARα-dependent and -independent peroxisome proliferators.…”