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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 mitochondrial function and abundance by HIF-α. (A) To adapt to low oxygen tension, cells undergo two HIF-1α-mediated alterations of cellular metabolism: O2-independent ATP production and reduction of mitochondrial O2 consumption. HIF-1α signaling also contributes to the Warburg effect of aerobic glycolysis—that is, an uncoupling of glycolysis from O2 levels—by stimulating the expression of the glucose transporter GLUT1 and glycolytic enzymes. Increased glycolysis generates increased levels of pyruvate, which is largely converted to lactate by HIF-inducible lactate dehydrogenase A (LDHA) and removed from the cell by the monocarboxylate transporter 4 (MCT4). HIF-1α induces pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and blocks conversion of pyruvate to acetyl-CoA, resulting in decreased flux through the tricarboxylic acid (TCA) cycle. Decreased TCA cycle activity attenuates oxidative phosphorylation and excessive mitochondrial ROS production. Under normoxia, COX4-1 is the predominant isoform of COX4 present in complex IV of the electron transport chain, which transfers electrons to O2. Under hypoxia, HIF-1α upregulates the expression of COX4-2 and the mitochondrial protease LONP1, which in turn degrades COX4-1. COX4-2 is more efficient at facilitating the electron transfer to O2 and thereby protects the cell from oxidative damage during hypoxia. (B) Control of mitochondrial biogenesis by HIF-α. HIF-1α induces the expression of MAX-interacting protein 1 (MXI1), a repressor of MYC activity, and thereby represses a subset of MYC target genes such as PGC-1β. HIF-1α-dependent activation of FOXO3a inhibits MYC activity by reducing MYC protein stability. Interaction between PGC-1 and transcription factors such as PPARα, ERR, and NRF-1/2 orchestrates the major functions of mitochondria. HIF-1α-mediated inhibition of MYC and PGC-1 results in reduced mitochondrial biogenesis.
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Figure 2: Regulation of mitochondrial function and abundance by HIF-α. (A) To adapt to low oxygen tension, cells undergo two HIF-1α-mediated alterations of cellular metabolism: O2-independent ATP production and reduction of mitochondrial O2 consumption. HIF-1α signaling also contributes to the Warburg effect of aerobic glycolysis—that is, an uncoupling of glycolysis from O2 levels—by stimulating the expression of the glucose transporter GLUT1 and glycolytic enzymes. Increased glycolysis generates increased levels of pyruvate, which is largely converted to lactate by HIF-inducible lactate dehydrogenase A (LDHA) and removed from the cell by the monocarboxylate transporter 4 (MCT4). HIF-1α induces pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and blocks conversion of pyruvate to acetyl-CoA, resulting in decreased flux through the tricarboxylic acid (TCA) cycle. Decreased TCA cycle activity attenuates oxidative phosphorylation and excessive mitochondrial ROS production. Under normoxia, COX4-1 is the predominant isoform of COX4 present in complex IV of the electron transport chain, which transfers electrons to O2. Under hypoxia, HIF-1α upregulates the expression of COX4-2 and the mitochondrial protease LONP1, which in turn degrades COX4-1. COX4-2 is more efficient at facilitating the electron transfer to O2 and thereby protects the cell from oxidative damage during hypoxia. (B) Control of mitochondrial biogenesis by HIF-α. HIF-1α induces the expression of MAX-interacting protein 1 (MXI1), a repressor of MYC activity, and thereby represses a subset of MYC target genes such as PGC-1β. HIF-1α-dependent activation of FOXO3a inhibits MYC activity by reducing MYC protein stability. Interaction between PGC-1 and transcription factors such as PPARα, ERR, and NRF-1/2 orchestrates the major functions of mitochondria. HIF-1α-mediated inhibition of MYC and PGC-1 results in reduced mitochondrial biogenesis.

Mentions: The hypoxia-dependent increase in the abundance and activity of HIF-1α and the HIF-1α-dependent transcriptional program have three major effects on metabolism that serve to equilibrate O2 consumption with O2 supply. First, HIF-1α promotes glycolytic energy production by inducing genes that encode glucose transporters (e.g., GLUT1, GLUT3) and glycolytic enzymes (Figure 2A) (Semenza, 2010). HIF-1α also upregulates lactate dehydrogenase A (LDHA), which converts pyruvate to lactate and regenerates NAD+ for continuous supply for glycolysis, and monocarboxylate transporter 4 (MCT4), which transports lactate out of the cell (Figure 2A).


Hypoxia signaling pathways: modulators of oxygen-related organelles.

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

Regulation of mitochondrial function and abundance by HIF-α. (A) To adapt to low oxygen tension, cells undergo two HIF-1α-mediated alterations of cellular metabolism: O2-independent ATP production and reduction of mitochondrial O2 consumption. HIF-1α signaling also contributes to the Warburg effect of aerobic glycolysis—that is, an uncoupling of glycolysis from O2 levels—by stimulating the expression of the glucose transporter GLUT1 and glycolytic enzymes. Increased glycolysis generates increased levels of pyruvate, which is largely converted to lactate by HIF-inducible lactate dehydrogenase A (LDHA) and removed from the cell by the monocarboxylate transporter 4 (MCT4). HIF-1α induces pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and blocks conversion of pyruvate to acetyl-CoA, resulting in decreased flux through the tricarboxylic acid (TCA) cycle. Decreased TCA cycle activity attenuates oxidative phosphorylation and excessive mitochondrial ROS production. Under normoxia, COX4-1 is the predominant isoform of COX4 present in complex IV of the electron transport chain, which transfers electrons to O2. Under hypoxia, HIF-1α upregulates the expression of COX4-2 and the mitochondrial protease LONP1, which in turn degrades COX4-1. COX4-2 is more efficient at facilitating the electron transfer to O2 and thereby protects the cell from oxidative damage during hypoxia. (B) Control of mitochondrial biogenesis by HIF-α. HIF-1α induces the expression of MAX-interacting protein 1 (MXI1), a repressor of MYC activity, and thereby represses a subset of MYC target genes such as PGC-1β. HIF-1α-dependent activation of FOXO3a inhibits MYC activity by reducing MYC protein stability. Interaction between PGC-1 and transcription factors such as PPARα, ERR, and NRF-1/2 orchestrates the major functions of mitochondria. HIF-1α-mediated inhibition of MYC and PGC-1 results in reduced mitochondrial biogenesis.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Regulation of mitochondrial function and abundance by HIF-α. (A) To adapt to low oxygen tension, cells undergo two HIF-1α-mediated alterations of cellular metabolism: O2-independent ATP production and reduction of mitochondrial O2 consumption. HIF-1α signaling also contributes to the Warburg effect of aerobic glycolysis—that is, an uncoupling of glycolysis from O2 levels—by stimulating the expression of the glucose transporter GLUT1 and glycolytic enzymes. Increased glycolysis generates increased levels of pyruvate, which is largely converted to lactate by HIF-inducible lactate dehydrogenase A (LDHA) and removed from the cell by the monocarboxylate transporter 4 (MCT4). HIF-1α induces pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and blocks conversion of pyruvate to acetyl-CoA, resulting in decreased flux through the tricarboxylic acid (TCA) cycle. Decreased TCA cycle activity attenuates oxidative phosphorylation and excessive mitochondrial ROS production. Under normoxia, COX4-1 is the predominant isoform of COX4 present in complex IV of the electron transport chain, which transfers electrons to O2. Under hypoxia, HIF-1α upregulates the expression of COX4-2 and the mitochondrial protease LONP1, which in turn degrades COX4-1. COX4-2 is more efficient at facilitating the electron transfer to O2 and thereby protects the cell from oxidative damage during hypoxia. (B) Control of mitochondrial biogenesis by HIF-α. HIF-1α induces the expression of MAX-interacting protein 1 (MXI1), a repressor of MYC activity, and thereby represses a subset of MYC target genes such as PGC-1β. HIF-1α-dependent activation of FOXO3a inhibits MYC activity by reducing MYC protein stability. Interaction between PGC-1 and transcription factors such as PPARα, ERR, and NRF-1/2 orchestrates the major functions of mitochondria. HIF-1α-mediated inhibition of MYC and PGC-1 results in reduced mitochondrial biogenesis.
Mentions: The hypoxia-dependent increase in the abundance and activity of HIF-1α and the HIF-1α-dependent transcriptional program have three major effects on metabolism that serve to equilibrate O2 consumption with O2 supply. First, HIF-1α promotes glycolytic energy production by inducing genes that encode glucose transporters (e.g., GLUT1, GLUT3) and glycolytic enzymes (Figure 2A) (Semenza, 2010). HIF-1α also upregulates lactate dehydrogenase A (LDHA), which converts pyruvate to lactate and regenerates NAD+ for continuous supply for glycolysis, and monocarboxylate transporter 4 (MCT4), which transports lactate out of the cell (Figure 2A).

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