Mitochondrial Plasticity and Glucose Metabolic Alterations in Human Cancer under Oxidative Stress-From Viewpoints of Chronic Inflammation and Neutrophil Extracellular Traps (NETs)

Abstract

Oxidative stress elicited by reactive oxygen species (ROS) and chronic inflammation are involved both in deterring and the generation/progression of human cancers. Exogenous ROS can injure mitochondria and induce them to generate more endogenous mitochondrial ROS to further perpetuate the deteriorating condition in the affected cells. Dysfunction of these cancer mitochondria may possibly be offset by the Warburg effect, which is characterized by amplified glycolysis and metabolic reprogramming. ROS from neutrophil extracellular traps (NETs) are an essential element for neutrophils to defend against invading pathogens or to kill cancer cells. A chronic inflammation typically includes consecutive NET activation and tissue damage, as well as tissue repair, and together with NETs, ROS would participate in both the destruction and progression of cancers. This review discusses human mitochondrial plasticity and the glucose metabolic reprogramming of cancer cells confronting oxidative stress by the means of chronic inflammation and neutrophil extracellular traps (NETs).

Keywords: Warburg effect; inflammation; mitochondrial plasticity; neutrophil; neutrophil extracellular traps (NETs); oxidative stress.

Figure 1

Glucose metabolism through glycolysis, Krebs cycle and OXPHOS to generate ATP, as well as electron leak and mtROS generation, are illustrated. α-KG: alpha-ketoglutarate; FAD: oxidized flavin adenine dinucleotide; FADH₂: reduced flavin adenine dinucleotide; HK: hexokinase; IMM: inner mitochondrial membrane; IMS: intermembrane space; LDH: lactate dehydrogenase; MMP: mitochondrial membrane potential; mtROS: mitochondrial ROS; NAD⁺: oxidized nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; OAA: oxaloacetate; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PDH: pyruvate dehydrogenase; ROS: reactive oxygen species.

Figure 2

Schematic illustration shows the underlying mechanism of chronic inflammation in carcinogenesis and cancer progression. 8-OHdG: 8-hydroxy-2′-deoxyguanosine; A: adenine; C: cytosine; DAMPs: damage-associated molecular patterns; G: guanine; HBV: hepatitis B virus; HP: Helicobacter pylori; HPV: human papillomavirus; Keap1-Nrf2-ARE: Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE); MAPK(s): mitogen-activated protein kinase(s); NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PAMPs: pathogen-associated molecular patterns; PI3K-Akt: phosphoinositide-3-kinase (PI3K)-Akt; PM2.5: particulate matter ≤ 2.5 µm; ROS: reactive oxygen species; T: thymine.

Figure 3

NETs formation includes NOX-dependent (through NOX-ROS) and NOX-independent (through mtROS) pathways. Most NETs are eliminated uneventfully after completing their tasks (left lower part). A NETs cascade might happen and cause several adverse effects to the host, including cancer progression (right lower part). ALI: acute lung injury; CitH: citrullinated histone; JNK: c-Jun N-terminal kinase; LPS: lipopolysaccharide; MPO: myeloperoxidase; mtROS: mitochondrial ROS; NE: neutrophil elastase; NETs: neutrophil extracellular traps; NOX: NADPH oxidase; PKC: protein kinase C; PMA: Phorbol 12-myristate 13-acetate; PPP: Pentose phosphate pathway; PAD4: protein arginine deiminase 4; ROS: reactive oxygen species.

Figure 4

Illustration of NETs, ROS, cancer mitochondrial oxidative damage and altered glucose metabolism, including the Warburg effect and glucose metabolic reprogramming, in human cancers is shown. Beneficial events from the Warburg effect are sketched and described in text sections, including 7.1: Increased antioxidant activity, 7.2: Rapid energy production, 7.3: Suppression of anticancer immunity and 7.4: Increased nucleic acid synthesis. Synthesis of macromolecules through glucose metabolic reprogramming is illustrated and described in text sections, including 8.1: Fatty acid synthesis, 8.2: Amino acid synthesis and 8.3: Nucleotide synthesis. 3PG: 3-phosphoglycerate; 3PHP: 3-phosphate hydroxypyruvate; 3-P-serine: 3-phosphoserine; 6PGD: 6-phosphogluconate dehydrogenase; 6PGL: 6-phosphogluconolactone; ACL: ATP-citrate lyase; α-KG: alpha-ketoglutarate; F: Folate; FADH₂: reduced flavin adenine dinucleotide; FR: folate reductase; G6P: glucose-6-phosphate; G6PD: glucose 6-phosphate dehydrogenase; GCS: Glycine cleavage system; GDS: glycine decarboxylase complex; GLS: glutaminase; GLUD: glutamate dehydrogenase; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: reduced glutathione; GSSG: oxidized glutathione; HK: hexokinase; LDH: lactate dehydrogenase; MTHFD: methylenetetrahydrofolate dehydrogenase/cyclohydrolase; mtROS: mitochondrial ROS; NAD⁺: oxidized nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; NADP⁺: oxidized nicotinamide adenine dinucleotide phosphate; NADPH: reduced nicotinamide adenine dinucleotide phosphate; NETs: neutrophil extracellular traps; OAA: oxaloacetate; PDH: pyruvate dehydrogenase; PEP: phosphoenolpyruvate; PHGDH: phosphoglycerate dehydrogenase; PPP: pentose phosphate pathway; PSAT1: phosphoserine aminotransferase; PSPH: 1–3-phosphoserine phosphatase; R5P: ribose 5-phosphate; ROS: reactive oxygen species; RPI: 5-phosphate isomerase; Ru5P: ribulose 5-phosphate; SHMT: serine hydroxymethyl transferase; SOD: superoxide dismutase; SSP: serine synthesis pathway; THF: tetrahydrofolate; TS: thymidylate synthase.

Figure 5

The regulation of mitochondrial biogenesis, including mtDNA regulation, mitochondrial dynamics and mitophagy, is illustrated. Drp1: dynamin-related protein 1; Fis1: human fission factor-1; MFF: mitochondrial fission factor; MFN1/2: mitofusin 1/2; mtDNA: mitochondrial DNA; nDNA: nuclear DNA; NRF1/2: nuclear respiratory factors 1/2; OPA1: optic atrophy factor 1; PGC-1α: peroxisome proliferators-activated receptor gamma coactivator-1α; MFN1/2: mitofusin 1/2; OPA1: optic atrophy factor 1; MFF: mitochondrial fission factor; PINK1: PTEN-induced kinase 1 (PINK1); TFAM: mitochondrial transcription factor A.

Figure 6

Local environment and the interactions between NETs and cancer are illustrated. CitH: citrullinated histone; cfDNA: cell free DNA; CXCL1/2/5: chemokine C-X-C motif ligand 1/2/5; Drp1: dynamin-related protein 1; HMGB1: high mobility group box 1; MFN1/2: mitofusin 1/2; MPO: myeloperoxidase; mtDNA: mitochondrial DNA; NE: neutrophil elastase; NETs: neutrophil extracellular traps; NRF1/2: nuclear respiratory factor 1/2; PAD4: protein arginine deiminase 4; PGC-1α: peroxisome proliferators-activated receptor gamma coactivator-1α; PINK1: PTEN-induced kinase 1; TFAM: mitochondrial transcription factor A.