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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

Regulation of HIF-α subunits. (A) Hypoxia-inducible factors (HIFs) are transcription factors composed of O2-regulated α subunits (HIF-1α or HIF-2α) and a constitutively expressed HIF-1β subunit. Together these subunits bind hypoxia response elements (HRE) to mediate adaptive responses to hypoxia. HIF-α activity is directly linked to oxygen partial pressure. Under normoxia, HIF-α is hydroxylated by prolyl hydroxylase domain protein (PHD) and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Under hypoxia, hydroxylation is inhibited and HIF-α is stabilized, it dimerizes with HIF-1β and enters the nucleus to induce target gene transcription. (B) HIF-α can be stabilized irrespective of O2 tension due to inhibition of PHDs, a state defined as pseudohypoxia. Mutations in the Krebs cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to accumulation of succinate and fumarate, respectively, whereas mutations in isocitrate dehydrogenases 1/2 (IDH1 and IDH2) lead to low levels of 2-oxoglutarate. Succinate and fumarate inhibit PHDs, while low levels of the co-substrate 2-oxoglutarate decrease the activity of PHDs. Decreased activity of PHDs leads to a low rate of HIF-α hydroxylation under normoxic conditions and stabilization of HIF-α.
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Figure 1: Regulation of HIF-α subunits. (A) Hypoxia-inducible factors (HIFs) are transcription factors composed of O2-regulated α subunits (HIF-1α or HIF-2α) and a constitutively expressed HIF-1β subunit. Together these subunits bind hypoxia response elements (HRE) to mediate adaptive responses to hypoxia. HIF-α activity is directly linked to oxygen partial pressure. Under normoxia, HIF-α is hydroxylated by prolyl hydroxylase domain protein (PHD) and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Under hypoxia, hydroxylation is inhibited and HIF-α is stabilized, it dimerizes with HIF-1β and enters the nucleus to induce target gene transcription. (B) HIF-α can be stabilized irrespective of O2 tension due to inhibition of PHDs, a state defined as pseudohypoxia. Mutations in the Krebs cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to accumulation of succinate and fumarate, respectively, whereas mutations in isocitrate dehydrogenases 1/2 (IDH1 and IDH2) lead to low levels of 2-oxoglutarate. Succinate and fumarate inhibit PHDs, while low levels of the co-substrate 2-oxoglutarate decrease the activity of PHDs. Decreased activity of PHDs leads to a low rate of HIF-α hydroxylation under normoxic conditions and stabilization of HIF-α.

Mentions: Central to the molecular mechanisms underlying O2 homeostasis are HIF-1α and HIF-2α that function as master regulators of the adaptive response to hypoxia. HIFs form a heterodimer consisting of a constitutively expressed ARNT/HIF-1β subunit and O2-regulated α subunits (HIF-1α or EPAS1/HIF-2α) (Majmundar et al., 2010; Keith et al., 2012). A third HIF-α subunit (HIF-3α) has also been described. HIF3A mRNA is differentially spliced to produce multiple HIF-3α isoforms that either promote or inhibit the activity of other HIF complexes (Keith et al., 2012). Under normoxia, HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1-3) and recognized and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex (Figure 1A). PHD enzymes are 2-oxoglutarate- and iron-dependent dioxygenases, whose activity is absolutely dependent on O2. Hence, the rate of HIF-α hydroxylation is suppressed under hypoxia. Hypoxia or loss of functional VHL stabilizes HIF-α subunits. HIF-α either dimerizes with HIF-1β and binds to hypoxia-responsive elements in promoters of target genes to promote a concerted transcriptional response (Keith et al., 2012) (Figure 1A) or it physically interacts with other non-HIF proteins (Uniacke et al., 2012; Hubbi et al., 2013), enabling convergence of HIF O2 sensing with other signaling pathways.


Hypoxia signaling pathways: modulators of oxygen-related organelles.

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

Regulation of HIF-α subunits. (A) Hypoxia-inducible factors (HIFs) are transcription factors composed of O2-regulated α subunits (HIF-1α or HIF-2α) and a constitutively expressed HIF-1β subunit. Together these subunits bind hypoxia response elements (HRE) to mediate adaptive responses to hypoxia. HIF-α activity is directly linked to oxygen partial pressure. Under normoxia, HIF-α is hydroxylated by prolyl hydroxylase domain protein (PHD) and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Under hypoxia, hydroxylation is inhibited and HIF-α is stabilized, it dimerizes with HIF-1β and enters the nucleus to induce target gene transcription. (B) HIF-α can be stabilized irrespective of O2 tension due to inhibition of PHDs, a state defined as pseudohypoxia. Mutations in the Krebs cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to accumulation of succinate and fumarate, respectively, whereas mutations in isocitrate dehydrogenases 1/2 (IDH1 and IDH2) lead to low levels of 2-oxoglutarate. Succinate and fumarate inhibit PHDs, while low levels of the co-substrate 2-oxoglutarate decrease the activity of PHDs. Decreased activity of PHDs leads to a low rate of HIF-α hydroxylation under normoxic conditions and stabilization of HIF-α.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Regulation of HIF-α subunits. (A) Hypoxia-inducible factors (HIFs) are transcription factors composed of O2-regulated α subunits (HIF-1α or HIF-2α) and a constitutively expressed HIF-1β subunit. Together these subunits bind hypoxia response elements (HRE) to mediate adaptive responses to hypoxia. HIF-α activity is directly linked to oxygen partial pressure. Under normoxia, HIF-α is hydroxylated by prolyl hydroxylase domain protein (PHD) and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Under hypoxia, hydroxylation is inhibited and HIF-α is stabilized, it dimerizes with HIF-1β and enters the nucleus to induce target gene transcription. (B) HIF-α can be stabilized irrespective of O2 tension due to inhibition of PHDs, a state defined as pseudohypoxia. Mutations in the Krebs cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to accumulation of succinate and fumarate, respectively, whereas mutations in isocitrate dehydrogenases 1/2 (IDH1 and IDH2) lead to low levels of 2-oxoglutarate. Succinate and fumarate inhibit PHDs, while low levels of the co-substrate 2-oxoglutarate decrease the activity of PHDs. Decreased activity of PHDs leads to a low rate of HIF-α hydroxylation under normoxic conditions and stabilization of HIF-α.
Mentions: Central to the molecular mechanisms underlying O2 homeostasis are HIF-1α and HIF-2α that function as master regulators of the adaptive response to hypoxia. HIFs form a heterodimer consisting of a constitutively expressed ARNT/HIF-1β subunit and O2-regulated α subunits (HIF-1α or EPAS1/HIF-2α) (Majmundar et al., 2010; Keith et al., 2012). A third HIF-α subunit (HIF-3α) has also been described. HIF3A mRNA is differentially spliced to produce multiple HIF-3α isoforms that either promote or inhibit the activity of other HIF complexes (Keith et al., 2012). Under normoxia, HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1-3) and recognized and targeted for proteasomal degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex (Figure 1A). PHD enzymes are 2-oxoglutarate- and iron-dependent dioxygenases, whose activity is absolutely dependent on O2. Hence, the rate of HIF-α hydroxylation is suppressed under hypoxia. Hypoxia or loss of functional VHL stabilizes HIF-α subunits. HIF-α either dimerizes with HIF-1β and binds to hypoxia-responsive elements in promoters of target genes to promote a concerted transcriptional response (Keith et al., 2012) (Figure 1A) or it physically interacts with other non-HIF proteins (Uniacke et al., 2012; Hubbi et al., 2013), enabling convergence of HIF O2 sensing with other signaling pathways.

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