Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

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

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.

Figures

Fig. 1
Fig. 1
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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