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

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Hif-2A Promotes Degradation of Mammalian Peroxisomes by Selective Autophagy Cell Metabolism Article Hif-2a Promotes Degradation of Mammalian Peroxisomes by Selective Autophagy Katharina M. Walter,1,2,10 Miriam J. Scho¨ nenberger,1,2,10 Martin Tro¨ tzmu¨ ller,3 Michael Horn,1 Hans-Peter Elsa¨ sser,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. Ko¨ feler,3 Wilhelm Krek,1,2,* and Werner J. Kovacs1,2,* 1Institute of Molecular Health Sciences 2Competence Center for Systems Physiology and Metabolic Diseases ETH Zurich, CH-8093 Zurich, Switzerland 3Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, A-8010 Graz, Austria 4Department of Cytobiology, Philipps-University Marburg, D-35037 Marburg, Germany 5Kennedy Krieger Institute, Baltimore, MD 21205, USA 6ScopeM – Scientific Center for Optical and Electron Microscopy, ETH Zurich, CH-8093 Zurich, Switzerland 7Division of Endocrinology and Diabetes, University Hospital Zurich, CH-8091 Zurich, Switzerland 8Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA 9Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland 10Co-first Authors *Correspondence: [email protected] (W.K.), [email protected] (W.J.K.) http://dx.doi.org/10.1016/j.cmet.2014.09.017 SUMMARY expressed HIF-1b subunit and O2-regulated a subunits (HIF-1a and HIF-2a)(Keith et al., 2012). Under normoxia, HIF-a subunits Peroxisomes play a central role in lipid metabolism, are hydroxylated and targeted for proteasomal degradation by and their function depends on molecular oxygen. an ubiquitin ligase complex containing the von Hippel-Lindau Low oxygen tension or von Hippel-Lindau (Vhl) tumor (VHL) tumor suppressor protein pVHL. Under hypoxia, HIF-a suppressor loss is known to stabilize hypoxia-induc- hydroxylation is inhibited, thereby stabilizing HIF-a protein. a b a ible factors alpha (Hif-1a and Hif-2a) to mediate HIF- dimerizes with HIF-1 to activate target genes. HIF-1 a adaptive responses, but it remains unknown if perox- and HIF-2 have both common and distinct target genes and are differentially regulated in various physiological and patho- isome homeostasis and metabolism are intercon- a physiological conditions, such as cancer and ischemic diseases nected with Hif- signaling. By studying liver-specific (Semenza, 2012; Keith et al., 2012). HIF-induced genes promote Vhl Vhl/Hif1a Vhl/Hif2a , , and knockout mice, we angiogenesis, erythropoiesis, metastasis, and metabolic reprog- demonstrate a regulatory function of Hif-2a signaling ramming, such as shifting metabolism from oxidative phos- on peroxisomes. Hif-2a activation augments peroxi- phorylation to glycolysis. Activation of HIFs also reprograms lipid some turnover by selective autophagy (pexophagy) metabolism leading to lipid accumulation (Kucejova et al., 2011; and thereby changes lipid composition reminiscent Qu et al., 2011; Kim et al., 2006; Rankin et al., 2009; Krishnan of peroxisomal disorders. The autophagy receptor et al., 2009), but it remains controversial how they promote lipid Nbr1 localizes to peroxisomes and is likewise deg- accumulation. a raded by Hif-2a-mediated pexophagy. Furthermore, Abundant evidence suggests key roles for HIF-1 in the regu- we demonstrate that peroxisome abundance is lation of mitochondrial metabolism (Semenza, 2011). However, so far there is no evidence linking HIF signaling to peroxisomes, reduced in VHL-deficient human clear cell renal cell whose function depends highly on molecular O . In fact, perox- carcinomas with high HIF-2a levels. These results 2 isomes may be responsible for as much as 20% of O2 consump- establish Hif-2a as a negative regulator of peroxi- tion and 35% of H2O2 production in tissues such as the liver some abundance and metabolism and suggest a (Fransen et al., 2012). Peroxisomes are extremely versatile and mechanism by which cells attune peroxisomal func- dynamic organelles whose number, size, and function are tion with oxygen availability. dependent on cell type and metabolic needs. They play key roles in the degradation of fatty acids (i.e., very long-chain fatty acids [VLCFAs] and polyunsaturated fatty acids [PUFAs]), ether lipid INTRODUCTION synthesis, cholesterol and bile acid synthesis, and metabolism of reactive oxygen species (Van Veldhoven, 2010; Faust and Ko- Oxygen (O2) is an essential substrate in cellular metabolism and vacs, 2014; Fransen et al., 2012). The importance of peroxisomal signaling and, as such, is inseparably linked to survival and metabolism is illustrated by peroxisome biogenesis disorders in normal function of all metazoan. Central to the molecular mech- which functional peroxisomes are absent or disorders caused by anisms underlying O2 homeostasis are hypoxia-inducible factors single peroxisomal enzyme deficiencies (Raymond et al., 2009). (HIFs) that function as master regulators of the adaptive response Lack of peroxisomal metabolism leads to extensive cellular to hypoxia. HIFs are heterodimers composed of a constitutively metabolic disarray, and patients with peroxisomal disorders, 882 Cell Metabolism 22, 882–897, November 4, 2014 ª2014 Elsevier Inc. Cell Metabolism Hif-2a Promotes Mammalian Pexophagy (legend on next page) Cell Metabolism 22, 882–897, November 4, 2014 ª2014 Elsevier Inc. 883 Cell Metabolism Hif-2a Promotes Mammalian Pexophagy as well as peroxisome-deficient mice, display severe hepatic To characterize the peroxisomal population in more detail, we dysfunction with fatty liver, cholestasis, and eventually cirrhosis isolated peroxisomes from control and VhlÀ/À livers (Figure S2A). (Raymond et al., 2009; Baes and Van Veldhoven, 2012; Faust Catalase activity was significantly decreased in postnuclear su- and Kovacs, 2014). pernatants from VhlÀ/À livers (Figure S2B). Peroxisomal protein Since peroxisomal function depends on O2, we hypothesized levels were significantly decreased in subcellular fractions from À/À that to minimize O2 consumption under hypoxic conditions, Vhl livers, whereas levels of the mitochondrial proteins HIF-a signaling may inhibit O2-dependent peroxisomal meta- Tomm20, Trap1, and Vdac were similar to controls (Figure S2C). bolism and/or decrease the number of peroxisomes. In addition, Immunoblots of gradient fractions from control livers showed HIF-mediated reduction in peroxisomal activity could promote that peroxisomes were enriched in fractions 17–20 (density metabolic reprogramming causing changes in lipid metabolism. range of 1.144–1.169 g/ml), whereas peroxisomal protein levels To test this hypothesis, we chose the mouse liver as model sys- were significantly decreased in gradient fractions from VhlÀ/À tem because peroxisomes are highly abundant in the liver, and livers (Figure S2D). The distribution pattern of catalase activity liver-specific loss of pVhl causes severe lipid accumulation. In displayed a major peak coincident with peroxisomal proteins in this study, we systematically investigated peroxisome homeo- control livers, and catalase activity was significantly decreased stasis and metabolism in wild-type and liver-specific Vhl, Vhl/ in VhlÀ/À livers (Figure S2E). These results argue for the presence Hif1a, and Vhl/Hif2a knockout mice and explored the role of of intact peroxisomes in VhlÀ/À livers, but the distribution pattern Hif-1a and Hif-2a in this context. of peroxisomal proteins suggests a heterogeneous peroxisome population. In summary, hepatic loss of Vhl function is associ- RESULTS ated with a reduction in peroxisome abundance. Peroxisome Abundance Is Reduced in Vhl–/– Livers Changes in Lipid Composition in Vhl–/– Livers Are To investigate whether peroxisomal abundance and/or meta- Reminiscent of Peroxisomal Disorders bolism are regulated by Hif-a, we inactivated the Vhl gene in Since peroxisomes play important roles in the degradation of the liver. As previously reported (Kucejova et al., 2011; Rankin VLCFAs and VLC-PUFAs, as well as in the synthesis of polyun- et al., 2009), 4-week-old (P28) liver-specific VhlÀ/À mice were saturated FAs, we investigated whether the decrease in peroxi- significantly smaller than control mice but had an increased liver some abundance had consequences on the lipid composition in to bodyweight ratio, displayed severe steatosis, were hypo- VhlÀ/À livers. We quantified the major lipid classes and the distri- glycemic, and Hif target gene expression was increased (Fig- bution of fatty acids within these classes in P28 control and ures S1A–S1G available online). Intriguingly, the protein levels VhlÀ/À livers and observed profound lipid alterations in VhlÀ/À of the peroxisomal matrix proteins catalase, acyl-CoA oxidase livers. The profile of triacylglycerol (TAG) species showed a (Acox1), multifunctional protein 1 (Mfp1), urate oxidase (Uox), disproportionate increase of TAGs with VLCFAs and VLC-PUFAs À/À as well as the peroxisomal membrane proteins Pex14p and in Vhl livers (Figures 1D and 1E; Table S1). C62 to C64 species Pex3p were significantly decreased in livers of P28 VhlÀ/À mice were hardly detectable in control livers but reached concentra- (Figure 1A), a phenomenon already evident at 2 weeks of age tions between 10–100 nmol/g liver tissue in VhlÀ/À livers. Most (Figure S1H). The effects of pVhl loss on peroxisomal protein TAG species showed an accumulation of 10-fold in VhlÀ/À levels were highly selective, as representative ER and mitochon- livers, but TAG species with a higher number of double bonds drial protein levels were similar in control
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