Limits...
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

Model illustrating the relationship between hypoxia, ER stress, and activation of the unfolded protein response. Severe hypoxic stress perturbs and reduces O2-dependent protein folding capacity, resulting in the accumulation and aggregation of misfolded proteins in the ER lumen. Hypoxia increases intracellular ROS production and ROS stimulate multiple biological responses during O2 deprivation. Unfolded proteins and hypoxic ROS trigger ER stress which leads to HIF-α-independent activation of the UPR. The UPR is initiated by the stress-sensing ER transmembrane proteins PERK, IRE1, and ATF6. The chaperone GRP78 is normally bound to these ER stress sensors and keeps them inactive, but dissociates from them under ER stress conditions. This dissociation leads to the activation of the three UPR pathways. GRP78 dissociation allows PERK to homodimerize, which facilitates autotransphosphorylation and kinase domain activation. Activated PERK phosphorylates eIF2α which decreases general translation while increasing the preferential translation of specific proteins, such as the transcription factor ATF4. ATF4 triggers the activation of a gene expression program referred to as the integrated stress response. ATF4 induces the expression of GADD34, which acts as a negative regulator of the PERK pathway by dephosphorylating eIF2α. The integrated stress response promotes energy and redox homeostasis and is an important prosurvival mechanism under moderate hypoxia. IRE1 homodimerization, followed by autotransphosphorylation, triggers its RNase activity. IRE1-mediated splicing of full-length XBP1 mRNA generates XBP1s, which encodes an active transcription factor. ER stress leads to the translocation of ATF6 to the Golgi, where it is cleaved by regulated intramembrane proteolysis to produce the active transcription factor. Modified from Faust and Kovacs (2014).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4508581&req=5

Figure 4: Model illustrating the relationship between hypoxia, ER stress, and activation of the unfolded protein response. Severe hypoxic stress perturbs and reduces O2-dependent protein folding capacity, resulting in the accumulation and aggregation of misfolded proteins in the ER lumen. Hypoxia increases intracellular ROS production and ROS stimulate multiple biological responses during O2 deprivation. Unfolded proteins and hypoxic ROS trigger ER stress which leads to HIF-α-independent activation of the UPR. The UPR is initiated by the stress-sensing ER transmembrane proteins PERK, IRE1, and ATF6. The chaperone GRP78 is normally bound to these ER stress sensors and keeps them inactive, but dissociates from them under ER stress conditions. This dissociation leads to the activation of the three UPR pathways. GRP78 dissociation allows PERK to homodimerize, which facilitates autotransphosphorylation and kinase domain activation. Activated PERK phosphorylates eIF2α which decreases general translation while increasing the preferential translation of specific proteins, such as the transcription factor ATF4. ATF4 triggers the activation of a gene expression program referred to as the integrated stress response. ATF4 induces the expression of GADD34, which acts as a negative regulator of the PERK pathway by dephosphorylating eIF2α. The integrated stress response promotes energy and redox homeostasis and is an important prosurvival mechanism under moderate hypoxia. IRE1 homodimerization, followed by autotransphosphorylation, triggers its RNase activity. IRE1-mediated splicing of full-length XBP1 mRNA generates XBP1s, which encodes an active transcription factor. ER stress leads to the translocation of ATF6 to the Golgi, where it is cleaved by regulated intramembrane proteolysis to produce the active transcription factor. Modified from Faust and Kovacs (2014).

Mentions: Activation of the three canonical branches of the UPR is mediated by three stress-sensing ER transmembrane proteins: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6) (Figure 4) (Walter and Ron, 2011; Faust and Kovacs, 2014). In a stress-free ER, these sensors are bound by the ER-resident chaperone glucose-regulated protein of 78 kDa (GRP78) in their intraluminal domains and rendered inactive. Upon ER stress, GRP78 dissociates from PERK, IRE1, and ATF6, leading to their activation (Bertolotti et al., 2000; Shen et al., 2002).


Hypoxia signaling pathways: modulators of oxygen-related organelles.

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

Model illustrating the relationship between hypoxia, ER stress, and activation of the unfolded protein response. Severe hypoxic stress perturbs and reduces O2-dependent protein folding capacity, resulting in the accumulation and aggregation of misfolded proteins in the ER lumen. Hypoxia increases intracellular ROS production and ROS stimulate multiple biological responses during O2 deprivation. Unfolded proteins and hypoxic ROS trigger ER stress which leads to HIF-α-independent activation of the UPR. The UPR is initiated by the stress-sensing ER transmembrane proteins PERK, IRE1, and ATF6. The chaperone GRP78 is normally bound to these ER stress sensors and keeps them inactive, but dissociates from them under ER stress conditions. This dissociation leads to the activation of the three UPR pathways. GRP78 dissociation allows PERK to homodimerize, which facilitates autotransphosphorylation and kinase domain activation. Activated PERK phosphorylates eIF2α which decreases general translation while increasing the preferential translation of specific proteins, such as the transcription factor ATF4. ATF4 triggers the activation of a gene expression program referred to as the integrated stress response. ATF4 induces the expression of GADD34, which acts as a negative regulator of the PERK pathway by dephosphorylating eIF2α. The integrated stress response promotes energy and redox homeostasis and is an important prosurvival mechanism under moderate hypoxia. IRE1 homodimerization, followed by autotransphosphorylation, triggers its RNase activity. IRE1-mediated splicing of full-length XBP1 mRNA generates XBP1s, which encodes an active transcription factor. ER stress leads to the translocation of ATF6 to the Golgi, where it is cleaved by regulated intramembrane proteolysis to produce the active transcription factor. Modified from Faust and Kovacs (2014).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Model illustrating the relationship between hypoxia, ER stress, and activation of the unfolded protein response. Severe hypoxic stress perturbs and reduces O2-dependent protein folding capacity, resulting in the accumulation and aggregation of misfolded proteins in the ER lumen. Hypoxia increases intracellular ROS production and ROS stimulate multiple biological responses during O2 deprivation. Unfolded proteins and hypoxic ROS trigger ER stress which leads to HIF-α-independent activation of the UPR. The UPR is initiated by the stress-sensing ER transmembrane proteins PERK, IRE1, and ATF6. The chaperone GRP78 is normally bound to these ER stress sensors and keeps them inactive, but dissociates from them under ER stress conditions. This dissociation leads to the activation of the three UPR pathways. GRP78 dissociation allows PERK to homodimerize, which facilitates autotransphosphorylation and kinase domain activation. Activated PERK phosphorylates eIF2α which decreases general translation while increasing the preferential translation of specific proteins, such as the transcription factor ATF4. ATF4 triggers the activation of a gene expression program referred to as the integrated stress response. ATF4 induces the expression of GADD34, which acts as a negative regulator of the PERK pathway by dephosphorylating eIF2α. The integrated stress response promotes energy and redox homeostasis and is an important prosurvival mechanism under moderate hypoxia. IRE1 homodimerization, followed by autotransphosphorylation, triggers its RNase activity. IRE1-mediated splicing of full-length XBP1 mRNA generates XBP1s, which encodes an active transcription factor. ER stress leads to the translocation of ATF6 to the Golgi, where it is cleaved by regulated intramembrane proteolysis to produce the active transcription factor. Modified from Faust and Kovacs (2014).
Mentions: Activation of the three canonical branches of the UPR is mediated by three stress-sensing ER transmembrane proteins: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6) (Figure 4) (Walter and Ron, 2011; Faust and Kovacs, 2014). In a stress-free ER, these sensors are bound by the ER-resident chaperone glucose-regulated protein of 78 kDa (GRP78) in their intraluminal domains and rendered inactive. Upon ER stress, GRP78 dissociates from PERK, IRE1, and ATF6, leading to their activation (Bertolotti et al., 2000; Shen et al., 2002).

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