Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism.

Dania C Liemburg-Apers,Werner J H Koopman,Sander Grefte,Peter H G M Willems

doi:10.1007/s00204-015-1520-y

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.

Highlights

Mitochondria are among the prime ATP-generating organelles, which are necessary for cellular functioning (Koop man et al 2012, 2013)
reactive oxygen species (ROS) are produced as a consequence of normal mitochondrial energy metabolism
When ROS levels are too high and/ or remain increased during a prolonged period of time, a vicious circle of ROS-stimulated glucose uptake and glucose-stimulated ROS production can be triggered. This pathological cycle can be broken by restoring mitochondrial ROS production to normal levels

Summary

Present Address

Department of Human and Animal Physiology, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands Abbreviations Δψ Mitochondrial membrane potential 4-HDDE 4-Hydroxydodecadienal 12-HPETE 12-Hydroperoxyeicosatetraenoic acid ASK1 Apoptosis signal-regulating kinase 1 AMPK AMP-activated protein kinase ANT Adenine nucleotide translocator ATM Ataxia telangiectasia mutated CI Complex I or NADH: ubiquinone oxidoreductase CII Complex II or succinate:ubiquinone oxidoreductase CIII Complex III or ubiquinol:cytochrome-c oxidoreductase CIV Complex IV or cytochrome-c oxidase Cu/ZnSOD Copper/zinc-dependent superoxide dismutase or SOD1 CV Complex V or F1Fo-ATP synthase chREBP Carbohydrate response element-binding protein CypD Cyclophilin D ETC Electron transport chain DHA Dehydroascorbic acid DHOH Dihydroorotate dehydrogenase FADH2 Reduced flavin adenine dinucleotide FMN Flavin mononucleotide G6PDH Glucose-6-phosphate-dehydrogenase GAPDH Glyceraldehyde-3-phosphate dehydrogenase GIPC1 Gα-interacting protein-interacting protein, C-terminus Glc/GO Glucose/glucose oxidase GLUT Glucose transporter Gpx Glutathione peroxidase Grx2 Glutaredoxin GSH Glutathione GSSG Oxidized glutathione HIF-1 Hypoxia-inducible factor-1 HK Hexokinase LDH Lactate dehydrogenase MAOs Monoamine oxidases MAPK p38 p38 mitogen-activated protein kinase MEFs Mouse embryonic fibroblasts mGPDH Sn-glycerol-3-phosphate dehydrogenase MIM Mitochondrial inner membrane MnSOD Manganese-dependent superoxide dismutase or SOD2 MOM Mitochondrial outer membrane PiC Inorganic phosphate carrier PTP Permeability transition pore NADH Reduced nicotinamide adenine dinucleotide NNT Nicotinamide nucleotide transhydrogenase Nox NAD(P)H oxidase ODDs Oxygen-dependent degradation domains Odh 2-Oxoglutarate dehydrogenase OXPHOS Oxidative phosphorylation PARP Poly(ADP-ribose) polymerase PDH Pyruvate dehydrogenase PHDs Prolyl-4-hydroxylases Pi Inorganic phosphate PI3K Phosphoinositide 3-kinase PIKK Phosphatidylinositol-3-kinase-related protein kinase PMF Proton motive force PPARδ Peroxisome proliferator-activated receptor δ PPP Pentose phosphate pathway Prx Peroxiredoxins RISP Rieske iron–sulfur protein ROS Reactive oxygen species SOD1 Copper/zinc-dependent superoxide dismutase or CuZnSOD SOD2 Manganese-dependent superoxide dismutase or MnSOD Sp1 Specificity protein TCA Tricarboxylic acid Trx Thioredoxin TXNIP Thioredoxin-interacting protein UCP Uncoupling protein Xan/XO Xanthine/xanthine oxidase

Introduction

Summary and conclusion