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Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism.

Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S - Arch. Toxicol. (2015)

Bottom Line: ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging.Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring.It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RUMC), P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

ABSTRACT
Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

No MeSH data available.


Related in: MedlinePlus

Interplay between ROS and glucose. a Glucose uptake can be regulated by: (1) altering the expression level of glucose transporters (GLUTs; blue), (2) stimulating translocation of GLUTs from internal vesicles to the plasma membrane and (3) changing the intrinsic activity of GLUTs at the plasma membrane. b Glycolytic conversion of glucose into pyruvate and subsequent pyruvate entry into the mitochondria (1) stimulates ROS production by hyperpolarizing the mitochondrial membrane potential (Δψ↑). Subsequently, ROS stimulate glucose uptake (see a), thereby triggering additional ROS production. Glucose flux through the pentose phosphate pathway (stimulated by AMPK and ATM) generates NADPH (2), which is an important cofactor in ROS scavenging. c Hyperpolarization of the mitochondrial membrane potential (Δψ↑) is prevented by: (1) GLUT1 internalization, (2) GLUT1 mRNA degradation, (3) reduction of pyruvate to lactate and subsequent secretion of lactate. A hyperpolarized mitochondrial membrane potential is diminished by: (4) transient uncoupling of the mitochondrial membrane potential (PTP, UCP) or enhancing oxidative phosphorylation efficiency by HK–CV interaction. Proteins that are activated by ROS are depicted in yellow (for details, see main text). 4-HDDE 4-hydroxydodecadienal, 12-HPETE 12-hydroperoxyeicosatetraenoic acid, Δψ mitochondrial membrane potential, ATM ataxia telangiectasia mutated, CV complex V, GIPC Gα-interacting protein-interacting protein, C-terminus, GLC glucose, Glut1 glucose transporter 1, HIF-1 hypoxia-inducible factor 1, HK hexokinase, LAC lactate, LDH lactate dehydrogenase, MCT monocarboxylate transporter, P-AMPK phosphorylated (activated) AMP-activated protein kinase, PHD prolyl hydroxylase domain, P-p38, phosphorylated (activated) p38 mitogen-activated protein kinase, PI3K phosphoinositide 3-kinase, PTP permeability transition pore, PYR pyruvate, ROS reactive oxygen species, TXNIP thioredoxin-interacting protein, UCP uncoupling protein (color figure online)
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Fig1: Interplay between ROS and glucose. a Glucose uptake can be regulated by: (1) altering the expression level of glucose transporters (GLUTs; blue), (2) stimulating translocation of GLUTs from internal vesicles to the plasma membrane and (3) changing the intrinsic activity of GLUTs at the plasma membrane. b Glycolytic conversion of glucose into pyruvate and subsequent pyruvate entry into the mitochondria (1) stimulates ROS production by hyperpolarizing the mitochondrial membrane potential (Δψ↑). Subsequently, ROS stimulate glucose uptake (see a), thereby triggering additional ROS production. Glucose flux through the pentose phosphate pathway (stimulated by AMPK and ATM) generates NADPH (2), which is an important cofactor in ROS scavenging. c Hyperpolarization of the mitochondrial membrane potential (Δψ↑) is prevented by: (1) GLUT1 internalization, (2) GLUT1 mRNA degradation, (3) reduction of pyruvate to lactate and subsequent secretion of lactate. A hyperpolarized mitochondrial membrane potential is diminished by: (4) transient uncoupling of the mitochondrial membrane potential (PTP, UCP) or enhancing oxidative phosphorylation efficiency by HK–CV interaction. Proteins that are activated by ROS are depicted in yellow (for details, see main text). 4-HDDE 4-hydroxydodecadienal, 12-HPETE 12-hydroperoxyeicosatetraenoic acid, Δψ mitochondrial membrane potential, ATM ataxia telangiectasia mutated, CV complex V, GIPC Gα-interacting protein-interacting protein, C-terminus, GLC glucose, Glut1 glucose transporter 1, HIF-1 hypoxia-inducible factor 1, HK hexokinase, LAC lactate, LDH lactate dehydrogenase, MCT monocarboxylate transporter, P-AMPK phosphorylated (activated) AMP-activated protein kinase, PHD prolyl hydroxylase domain, P-p38, phosphorylated (activated) p38 mitogen-activated protein kinase, PI3K phosphoinositide 3-kinase, PTP permeability transition pore, PYR pyruvate, ROS reactive oxygen species, TXNIP thioredoxin-interacting protein, UCP uncoupling protein (color figure online)

Mentions: HIF-1 consists of two subunits, HIF-1α and HIF-1β. Under normoxic conditions, prolines within the oxygen-dependent degradation domains (ODDs) of HIF-1α are hydroxylated by prolyl-4-hydroxylases (PHDs; Ivan et al. 2001). This hydroxylation acts as an ubiquitination signal leading to proteasomal degradation of HIF-1α. In the absence of oxygen, HIF-1α ubiquitinylation is inhibited allowing its interaction with HIF-1β to drive transcription of various target genes, including GLUT1 (Hayashi et al. 2004; Iyer et al. 1998; Ouiddir et al. 1999; Wood et al. 1998). During hypoxia, ROS levels increase and play an important role in HIF-1α stabilization (Brunelle et al. 2005; Chandel et al. 2000; Guzy et al. 2005; Mansfield et al. 2005; Sanjuan-Pla et al. 2005; Schroedl et al. 2002). Preventing ROS-mediated HIF-1α stabilization represses GLUT1 expression and glucose uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells (Jung et al. 2013). Upon mitochondrial DNA depletion (Chandel et al. 2000; Mansfield et al. 2005) and in mouse embryonic fibroblasts (MEFs) lacking cytochrome-c (Mansfield et al. 2005), hypoxia-induced HIF-1α stabilization is abrogated. This suggests that hypoxia-induced ROS are of mitochondrial origin. Knockout of the Rieske iron–sulfur protein (RISP) in mitochondrial CIII decreases ROS production during hypoxia and attenuates hypoxic stabilization of HIF-1α (Guzy et al. 2005). Therefore, RISP-mediated mitochondrial ROS production appears to be involved in HIF-1α stabilization during hypoxia. At the RISP site, electrons are transferred one-by-one from ubiquinol to cytochrome-c1. This one-electron donation generates a highly reactive ubisemiquinone, which can act as a source for superoxide generation. Over-expression of catalase (Chandel et al. 2000; Guzy et al. 2005) or GPx1 (Brunelle et al. 2005; Emerling et al. 2005) abolishes HIF-1α stabilization during hypoxia, whereas over-expression of SOD1 or SOD2 does not (Brunelle et al. 2005; Guzy et al. 2005). In addition, exogenous hydrogen peroxide is sufficient to stabilize HIF-1α under normoxic conditions (Chandel et al. 2000; Jung et al. 2008; Mansfield et al. 2005). This suggests that the stabilization of HIF-1α primarily involves hydrogen peroxide via inactivation of PHDs (Fig. 1a) and subsequent reduction of HIF-1α ubiquitinylation (Chandel et al. 1998; Guzy and Schumacker 2006). However, HIF-1α ubiquitinylation is incompletely blocked by exogenous or hypoxia-derived hydrogen peroxide (Guzy et al. 2005), suggesting the involvement of additional mechanisms.Fig. 1


Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism.

Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S - Arch. Toxicol. (2015)

Interplay between ROS and glucose. a Glucose uptake can be regulated by: (1) altering the expression level of glucose transporters (GLUTs; blue), (2) stimulating translocation of GLUTs from internal vesicles to the plasma membrane and (3) changing the intrinsic activity of GLUTs at the plasma membrane. b Glycolytic conversion of glucose into pyruvate and subsequent pyruvate entry into the mitochondria (1) stimulates ROS production by hyperpolarizing the mitochondrial membrane potential (Δψ↑). Subsequently, ROS stimulate glucose uptake (see a), thereby triggering additional ROS production. Glucose flux through the pentose phosphate pathway (stimulated by AMPK and ATM) generates NADPH (2), which is an important cofactor in ROS scavenging. c Hyperpolarization of the mitochondrial membrane potential (Δψ↑) is prevented by: (1) GLUT1 internalization, (2) GLUT1 mRNA degradation, (3) reduction of pyruvate to lactate and subsequent secretion of lactate. A hyperpolarized mitochondrial membrane potential is diminished by: (4) transient uncoupling of the mitochondrial membrane potential (PTP, UCP) or enhancing oxidative phosphorylation efficiency by HK–CV interaction. Proteins that are activated by ROS are depicted in yellow (for details, see main text). 4-HDDE 4-hydroxydodecadienal, 12-HPETE 12-hydroperoxyeicosatetraenoic acid, Δψ mitochondrial membrane potential, ATM ataxia telangiectasia mutated, CV complex V, GIPC Gα-interacting protein-interacting protein, C-terminus, GLC glucose, Glut1 glucose transporter 1, HIF-1 hypoxia-inducible factor 1, HK hexokinase, LAC lactate, LDH lactate dehydrogenase, MCT monocarboxylate transporter, P-AMPK phosphorylated (activated) AMP-activated protein kinase, PHD prolyl hydroxylase domain, P-p38, phosphorylated (activated) p38 mitogen-activated protein kinase, PI3K phosphoinositide 3-kinase, PTP permeability transition pore, PYR pyruvate, ROS reactive oxygen species, TXNIP thioredoxin-interacting protein, UCP uncoupling protein (color figure online)
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Fig1: Interplay between ROS and glucose. a Glucose uptake can be regulated by: (1) altering the expression level of glucose transporters (GLUTs; blue), (2) stimulating translocation of GLUTs from internal vesicles to the plasma membrane and (3) changing the intrinsic activity of GLUTs at the plasma membrane. b Glycolytic conversion of glucose into pyruvate and subsequent pyruvate entry into the mitochondria (1) stimulates ROS production by hyperpolarizing the mitochondrial membrane potential (Δψ↑). Subsequently, ROS stimulate glucose uptake (see a), thereby triggering additional ROS production. Glucose flux through the pentose phosphate pathway (stimulated by AMPK and ATM) generates NADPH (2), which is an important cofactor in ROS scavenging. c Hyperpolarization of the mitochondrial membrane potential (Δψ↑) is prevented by: (1) GLUT1 internalization, (2) GLUT1 mRNA degradation, (3) reduction of pyruvate to lactate and subsequent secretion of lactate. A hyperpolarized mitochondrial membrane potential is diminished by: (4) transient uncoupling of the mitochondrial membrane potential (PTP, UCP) or enhancing oxidative phosphorylation efficiency by HK–CV interaction. Proteins that are activated by ROS are depicted in yellow (for details, see main text). 4-HDDE 4-hydroxydodecadienal, 12-HPETE 12-hydroperoxyeicosatetraenoic acid, Δψ mitochondrial membrane potential, ATM ataxia telangiectasia mutated, CV complex V, GIPC Gα-interacting protein-interacting protein, C-terminus, GLC glucose, Glut1 glucose transporter 1, HIF-1 hypoxia-inducible factor 1, HK hexokinase, LAC lactate, LDH lactate dehydrogenase, MCT monocarboxylate transporter, P-AMPK phosphorylated (activated) AMP-activated protein kinase, PHD prolyl hydroxylase domain, P-p38, phosphorylated (activated) p38 mitogen-activated protein kinase, PI3K phosphoinositide 3-kinase, PTP permeability transition pore, PYR pyruvate, ROS reactive oxygen species, TXNIP thioredoxin-interacting protein, UCP uncoupling protein (color figure online)
Mentions: HIF-1 consists of two subunits, HIF-1α and HIF-1β. Under normoxic conditions, prolines within the oxygen-dependent degradation domains (ODDs) of HIF-1α are hydroxylated by prolyl-4-hydroxylases (PHDs; Ivan et al. 2001). This hydroxylation acts as an ubiquitination signal leading to proteasomal degradation of HIF-1α. In the absence of oxygen, HIF-1α ubiquitinylation is inhibited allowing its interaction with HIF-1β to drive transcription of various target genes, including GLUT1 (Hayashi et al. 2004; Iyer et al. 1998; Ouiddir et al. 1999; Wood et al. 1998). During hypoxia, ROS levels increase and play an important role in HIF-1α stabilization (Brunelle et al. 2005; Chandel et al. 2000; Guzy et al. 2005; Mansfield et al. 2005; Sanjuan-Pla et al. 2005; Schroedl et al. 2002). Preventing ROS-mediated HIF-1α stabilization represses GLUT1 expression and glucose uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells (Jung et al. 2013). Upon mitochondrial DNA depletion (Chandel et al. 2000; Mansfield et al. 2005) and in mouse embryonic fibroblasts (MEFs) lacking cytochrome-c (Mansfield et al. 2005), hypoxia-induced HIF-1α stabilization is abrogated. This suggests that hypoxia-induced ROS are of mitochondrial origin. Knockout of the Rieske iron–sulfur protein (RISP) in mitochondrial CIII decreases ROS production during hypoxia and attenuates hypoxic stabilization of HIF-1α (Guzy et al. 2005). Therefore, RISP-mediated mitochondrial ROS production appears to be involved in HIF-1α stabilization during hypoxia. At the RISP site, electrons are transferred one-by-one from ubiquinol to cytochrome-c1. This one-electron donation generates a highly reactive ubisemiquinone, which can act as a source for superoxide generation. Over-expression of catalase (Chandel et al. 2000; Guzy et al. 2005) or GPx1 (Brunelle et al. 2005; Emerling et al. 2005) abolishes HIF-1α stabilization during hypoxia, whereas over-expression of SOD1 or SOD2 does not (Brunelle et al. 2005; Guzy et al. 2005). In addition, exogenous hydrogen peroxide is sufficient to stabilize HIF-1α under normoxic conditions (Chandel et al. 2000; Jung et al. 2008; Mansfield et al. 2005). This suggests that the stabilization of HIF-1α primarily involves hydrogen peroxide via inactivation of PHDs (Fig. 1a) and subsequent reduction of HIF-1α ubiquitinylation (Chandel et al. 1998; Guzy and Schumacker 2006). However, HIF-1α ubiquitinylation is incompletely blocked by exogenous or hypoxia-derived hydrogen peroxide (Guzy et al. 2005), suggesting the involvement of additional mechanisms.Fig. 1

Bottom Line: ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging.Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring.It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RUMC), P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

ABSTRACT
Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

No MeSH data available.


Related in: MedlinePlus