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Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus

(A) The major metabolic pathways in peroxisomes of the mammalian liver. Various lipids are transported by PMPs (e.g., the ABC transporter proteins ABCD1, ABCD2, ABCD3) into the peroxisomal matrix, where they are oxidized by the β-oxidation enzymes. The products of the β-oxidation can serve as substrates for the biosynthesis of ether-linked phospholipids, cholesterol and bile acids or may exit the peroxisome for further oxidation in mitochondria. With regard to PUFAs, peroxisomes not only degrade these compounds but are also involved in their formation through retroconversion of PUFAs by catalyzing the chain-shortening steps. Peroxisomal function depends highly on molecular O2 due to its oxidative type of metabolism. Peroxisomal β-oxidation and the activity of other peroxisomal oxidases (e.g., UOX, DAO) result in the production of H2O2, which is decomposed by catalase. Modified from Schrader and Fahimi (2008). (B) Model for HIF-2α-mediated decrease in peroxisome abundance. Peroxisome homeostasis is achieved by balancing biogenesis and degradation of peroxisomes. HIF-2α signaling promotes degradation of peroxisomes by pexophagy. Reduced peroxisome abundance and the ensuing deficiency in peroxisomal function leads to major changes in the lipid profile, such as accumulation of VLCFAs. VLCFAs are activating ligands for the transcription factor PPARα. HIF-2α represses ligand-induced PPARα-mediated peroxisome proliferation and consequential restoration of peroxisome homeostasis. Thus, by simultaneously inducing pexophagy and counteracting PPARα, HIF-2α ensures efficient depletion of the peroxisome pool.
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Figure 5: (A) The major metabolic pathways in peroxisomes of the mammalian liver. Various lipids are transported by PMPs (e.g., the ABC transporter proteins ABCD1, ABCD2, ABCD3) into the peroxisomal matrix, where they are oxidized by the β-oxidation enzymes. The products of the β-oxidation can serve as substrates for the biosynthesis of ether-linked phospholipids, cholesterol and bile acids or may exit the peroxisome for further oxidation in mitochondria. With regard to PUFAs, peroxisomes not only degrade these compounds but are also involved in their formation through retroconversion of PUFAs by catalyzing the chain-shortening steps. Peroxisomal function depends highly on molecular O2 due to its oxidative type of metabolism. Peroxisomal β-oxidation and the activity of other peroxisomal oxidases (e.g., UOX, DAO) result in the production of H2O2, which is decomposed by catalase. Modified from Schrader and Fahimi (2008). (B) Model for HIF-2α-mediated decrease in peroxisome abundance. Peroxisome homeostasis is achieved by balancing biogenesis and degradation of peroxisomes. HIF-2α signaling promotes degradation of peroxisomes by pexophagy. Reduced peroxisome abundance and the ensuing deficiency in peroxisomal function leads to major changes in the lipid profile, such as accumulation of VLCFAs. VLCFAs are activating ligands for the transcription factor PPARα. HIF-2α represses ligand-induced PPARα-mediated peroxisome proliferation and consequential restoration of peroxisome homeostasis. Thus, by simultaneously inducing pexophagy and counteracting PPARα, HIF-2α ensures efficient depletion of the peroxisome pool.

Mentions: Peroxisomes are ubiquitous and highly dynamic organelles whose number, size, and function are 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), branched-chain FAs, polyunsaturated FAs (PUFAs)], ether lipid synthesis, cholesterol and bile acid synthesis, and metabolism of ROS (Figure 5A) (Van Veldhoven, 2010; Fransen et al., 2012; Faust and Kovacs, 2014). They also act as intracellular signaling platforms in redox, lipid, inflammatory, and innate immunity signaling (Dixit et al., 2010; Nordgren and Fransen, 2014; Odendall et al., 2014). The importance of peroxisomes for cellular metabolism is illustrated by the marked abnormalities in brain and systemic organs in peroxisome biogenesis disorders of the Zellweger spectrum in which functional peroxisomes are absent and disorders caused by single peroxisomal enzyme deficiencies (Raymond et al., 2009). Lack of peroxisomal metabolism creates severe biochemical abnormalities, leading to a variety of clinical symptoms both in patients with peroxisomal disorders as well as peroxisome-deficient mice (Kovacs et al., 2002; Raymond et al., 2009; Baes and Van Veldhoven, 2012; Faust and Kovacs, 2014).


Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

(A) The major metabolic pathways in peroxisomes of the mammalian liver. Various lipids are transported by PMPs (e.g., the ABC transporter proteins ABCD1, ABCD2, ABCD3) into the peroxisomal matrix, where they are oxidized by the β-oxidation enzymes. The products of the β-oxidation can serve as substrates for the biosynthesis of ether-linked phospholipids, cholesterol and bile acids or may exit the peroxisome for further oxidation in mitochondria. With regard to PUFAs, peroxisomes not only degrade these compounds but are also involved in their formation through retroconversion of PUFAs by catalyzing the chain-shortening steps. Peroxisomal function depends highly on molecular O2 due to its oxidative type of metabolism. Peroxisomal β-oxidation and the activity of other peroxisomal oxidases (e.g., UOX, DAO) result in the production of H2O2, which is decomposed by catalase. Modified from Schrader and Fahimi (2008). (B) Model for HIF-2α-mediated decrease in peroxisome abundance. Peroxisome homeostasis is achieved by balancing biogenesis and degradation of peroxisomes. HIF-2α signaling promotes degradation of peroxisomes by pexophagy. Reduced peroxisome abundance and the ensuing deficiency in peroxisomal function leads to major changes in the lipid profile, such as accumulation of VLCFAs. VLCFAs are activating ligands for the transcription factor PPARα. HIF-2α represses ligand-induced PPARα-mediated peroxisome proliferation and consequential restoration of peroxisome homeostasis. Thus, by simultaneously inducing pexophagy and counteracting PPARα, HIF-2α ensures efficient depletion of the peroxisome pool.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508581&req=5

Figure 5: (A) The major metabolic pathways in peroxisomes of the mammalian liver. Various lipids are transported by PMPs (e.g., the ABC transporter proteins ABCD1, ABCD2, ABCD3) into the peroxisomal matrix, where they are oxidized by the β-oxidation enzymes. The products of the β-oxidation can serve as substrates for the biosynthesis of ether-linked phospholipids, cholesterol and bile acids or may exit the peroxisome for further oxidation in mitochondria. With regard to PUFAs, peroxisomes not only degrade these compounds but are also involved in their formation through retroconversion of PUFAs by catalyzing the chain-shortening steps. Peroxisomal function depends highly on molecular O2 due to its oxidative type of metabolism. Peroxisomal β-oxidation and the activity of other peroxisomal oxidases (e.g., UOX, DAO) result in the production of H2O2, which is decomposed by catalase. Modified from Schrader and Fahimi (2008). (B) Model for HIF-2α-mediated decrease in peroxisome abundance. Peroxisome homeostasis is achieved by balancing biogenesis and degradation of peroxisomes. HIF-2α signaling promotes degradation of peroxisomes by pexophagy. Reduced peroxisome abundance and the ensuing deficiency in peroxisomal function leads to major changes in the lipid profile, such as accumulation of VLCFAs. VLCFAs are activating ligands for the transcription factor PPARα. HIF-2α represses ligand-induced PPARα-mediated peroxisome proliferation and consequential restoration of peroxisome homeostasis. Thus, by simultaneously inducing pexophagy and counteracting PPARα, HIF-2α ensures efficient depletion of the peroxisome pool.
Mentions: Peroxisomes are ubiquitous and highly dynamic organelles whose number, size, and function are 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), branched-chain FAs, polyunsaturated FAs (PUFAs)], ether lipid synthesis, cholesterol and bile acid synthesis, and metabolism of ROS (Figure 5A) (Van Veldhoven, 2010; Fransen et al., 2012; Faust and Kovacs, 2014). They also act as intracellular signaling platforms in redox, lipid, inflammatory, and innate immunity signaling (Dixit et al., 2010; Nordgren and Fransen, 2014; Odendall et al., 2014). The importance of peroxisomes for cellular metabolism is illustrated by the marked abnormalities in brain and systemic organs in peroxisome biogenesis disorders of the Zellweger spectrum in which functional peroxisomes are absent and disorders caused by single peroxisomal enzyme deficiencies (Raymond et al., 2009). Lack of peroxisomal metabolism creates severe biochemical abnormalities, leading to a variety of clinical symptoms both in patients with peroxisomal disorders as well as peroxisome-deficient mice (Kovacs et al., 2002; Raymond et al., 2009; Baes and Van Veldhoven, 2012; Faust and Kovacs, 2014).

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus