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Review
. 2021 Jun 1;34(16):1319-1354.
doi: 10.1089/ars.2020.8161.

Interplay Between Reactive Oxygen/Reactive Nitrogen Species and Metabolism in Vascular Biology and Disease

Masuko Ushio-Fukai  1   2 , Dipankar Ash  1   2 , Sheela Nagarkoti  1   2 , Eric J Belin de Chantemèle  1   2 , David J R Fulton  1   3 , Tohru Fukai  1   3   4
Affiliations
Review

Interplay Between Reactive Oxygen/Reactive Nitrogen Species and Metabolism in Vascular Biology and Disease

Masuko Ushio-Fukai et al. Antioxid Redox Signal. .

Abstract

Reactive oxygen species (ROS; e.g., superoxide [O2•-] and hydrogen peroxide [H2O2]) and reactive nitrogen species (RNS; e.g., nitric oxide [NO•]) at the physiological level function as signaling molecules that mediate many biological responses, including cell proliferation, migration, differentiation, and gene expression. By contrast, excess ROS/RNS, a consequence of dysregulated redox homeostasis, is a hallmark of cardiovascular disease. Accumulating evidence suggests that both ROS and RNS regulate various metabolic pathways and enzymes. Recent studies indicate that cells have mechanisms that fine-tune ROS/RNS levels by tight regulation of metabolic pathways, such as glycolysis and oxidative phosphorylation. The ROS/RNS-mediated inhibition of glycolytic pathways promotes metabolic reprogramming away from glycolytic flux toward the oxidative pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant defense. This review summarizes our current knowledge of the mechanisms by which ROS/RNS regulate metabolic enzymes and cellular metabolism and how cellular metabolism influences redox homeostasis and the pathogenesis of disease. A full understanding of these mechanisms will be important for the development of new therapeutic strategies to treat diseases associated with dysregulated redox homeostasis and metabolism. Antioxid. Redox Signal. 34, 1319-1354.

Keywords: metabolism; oxidative stress; reactive nitrogen species; reactive oxygen species; redox signaling.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

FIG. 1.
FIG. 1.
Role of metabolism in cellular function. Metabolism regulates cellular function by integrating energy production, biosynthesis, control of redox state, cell signaling, and transcription. The main metabolic task is to produce ATP to meet energetic demands for cellular function via glycolysis, oxidative phosphorylation and the TCA cycle. Metabolism is also necessary for biosynthetic pathways, including the PPP for nucleotide synthesis, as well as the glycerolipid synthesis pathway (lipid synthesis) and serine biosynthesis pathway. Metabolic pathways also regulate the intracellular redox state by controlling NAD(P)+/NAD(P)H pools and GSH to fuel the TRX/GSH antioxidant defense system. NADPH is derived from PPP, IDHs, MEs, and 1C metabolism, whereas GSH is derived from glutaminolysis. Further, metabolism regulates ETC to produce mitoROS. Finally, metabolism influences signaling and transcription by regulating post-translational modification (e.g., glycosylation via the hexosamine biosynthetic pathway), epigenetic modification, and metabolite signaling. 1C, one-carbon; ATP, adenosine triphosphate; ETC, electron transport chain; GSH, glutathione; ME, malic enzyme; mitoROS, mitochondrial ROS; NADPH, nicotinamide adenine dinucleotide phosphate; PPP, pentose phosphate pathway; ROS, reactive oxygen species; TCA, tricarboxylic acid; TRX, thioredoxin. Color images are available online.
FIG. 2.
FIG. 2.
Generation and metabolism of ROS/RNS. O2•− is produced by NOXs, the mitochondrial ETC, XO, lipoxygenase, cyclooxygenase, and uncoupled NOS. O2•− is converted by SODs to H2O2, which, in turn, is reduced to water via the actions of catalase, GPXs, and PRXs. The PRX/TRX and GPX/GSH systems are fueled by NADPH, which is generated by the PPP, IDHs, MEs, and 1C metabolism. Of note, NADPH is also a substrate for the ROS-generating NOXs and NOS. In the presence of reduced transition metals (Fe2+ and Cu2+), H2O2 undergoes spontaneous conversion to reactive OH• or related metal-associated reactive species. NO• is produced by coupled NOS. The NOS enzymes utilize NADPH and l-arginine as co-substrates and BH4 (a product of 1C metabolism) as essential co-factors. Although all NOS isoforms generate NO•, they can also generate O2•− at the expense of NO• via a process known as uncoupling. The mechanisms underlying the uncoupling process include the formation of monomers, altered Hsp90 binding, and insufficient levels of BH4 and l-arginine. Importantly, NO• can be rapidly inactivated via a reaction with O2•−, which leads to the formation of the strong oxidant, ONOO−. Thus, SODs are the first line of defense against O2•−-mediated toxicity. The SODs also participate in cell signaling events via their capacity to regulate levels of ROS (e.g., O2•−, H2O2) while preserving available NO•. BH4, tetrahydrobiopterin; GPX, glutathione peroxidase; H2O2, hydrogen peroxide; Hsp, heat-shock protein; NO•, nitric oxide; NOS, nitric oxide synthase; NOX, NADPH oxidase; O2•−, superoxide; OH•, hydroxyl radical; ONOO−, peroxynitrite; PRX, peroxiredoxin; RNS, reactive nitrogen species; SOD, superoxide dismutase; XO, xanthine oxidase. Color images are available online.
FIG. 3.
FIG. 3.
Interplay between mitoROS production, the ETC, and the TCA cycle. mitoROS are produced by the ETC at complexes I and III during oxidative phosphorylation. The reducing equivalents NADH and FADH2, which are generated by the TCA cycle in a series of enzymatic reactions, transfer electrons to the ETC to produce ATP. Thus, mitoROS, the ETC, and the TCA cycle are closely connected during oxidative phosphorylation. When the pool of CoQ is reduced, mitoROS are produced by complex I via RET. Further, VDACs control the release of O2•− from the mitochondria to the cytosol. NADH is produced during the conversion of α-α-KG to succinyl CoA to provide electrons for complex I in the ETC. NADH is also produced in the conversion of isocitrate to α-KG and the conversion of malate to OAA in the TCA cycle. FADH2 is produced during the conversion of succinate to fumarate via the actions of SDH, which is an enzyme that participates in both the TCA cycle and the ETC. α-KG, α-ketoglutarate; CoA, coenzyme A; complex I, NADH–ubiquinone oxidoreductase; complex III, ubiquinol–cytochrome c oxidoreductase; coQ, coenzyme Q; Cyt c: cytochrome c; FADH2, reduced flavin adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; OAA, oxaloacetate; RET, reverse electron transport; SDH, succinate dehydrogenase; VDAC, voltage-dependent anion channel. Color images are available online.
FIG. 4.
FIG. 4.
Cellular metabolic pathway involved in redox homeostasis. The major metabolic pathways that regulate redox homeostasis in ECs are as shown. Parts of metabolic pathways that take place in immune cells (e.g., those involving itaconate) are also included. Metabolic pathways that regulate redox homeostasis are limited to those involved in the production of NADPH and GSH (shown in green) and that regulate eNOS activity (shown in red). The ECs primarily utilize glycolysis (shaded in green) to obtain ATP. During this process, ECs generate pyruvate and lactate from glucose, thereby contributing to four additional pathways. The first of these, known as the PPP (shaded in yellow), includes both oxPPP and non-oxPPP pathways that contribute to antioxidant defense and nucleotide synthesis, respectively. Second, 1C metabolism (shaded in gray) contributes to protein and nucleotide methylation. Third, the hexosamine pathway (shaded in blue) uses F6P to promote protein glycosylation and synthesis of the luminal glycocalyx. Finally, after glycolysis, pyruvate can enter the mitochondria where it is converted to acetyl-CoA and can then enter the TCA cycle (shown in purple). NADPH is essential not only for antioxidant defense pathways, including the PRX/TRX and GPX/GSH systems that mitigate ROS-related cellular damage, but it is also necessary for the generation of NO• (a cofactor for NOS) and O2•− (a cofactor of the NOX enzymes). The major metabolic pathways that generate NADPH include oxPPP, ME1, 1C metabolism, IDH1/2, glutamine metabolism, and CPT1-mediated FAO. De novo synthesis of the antioxidant, GSH (shown in green) involves CySS import into the cell via the CySS/glutamate transporter (xCT), cysteine generated from methionine via the transsulfuration pathway, and glutamine metabolism. Cysteine is also involved in the synthesis of the gaseous transmitter, H2S. The primary metabolic pathways contributing to coupled and uncoupled eNOS include the ornithine cycle (shaded in pink), the mevalonate pathway (shaded in pale blue), and 1C metabolism (via BH4). Lastly, itaconate synthesized from aconitate in activated macrophages via the actions of IRG1 inhibits the activity of SDH. This inhibits ROS generation by RET at complex I. CPT1, carnitine palmitoyltransferase-1; CySS, cystine; EC, endothelial cell; eNOS, endothelial NOS; FAO, fatty acid oxidation; H2S, hydrogen sulfide; IRG1, immune-responsive gene 1; LDH, lactate dehydrogenase; oxPPP, oxidative PPP; xCT, the cystine/glutamate antiporter SLC7A11. Color images are available online.
FIG. 5.
FIG. 5.
Interplay between ROS and cellular metabolic pathways. Metabolic pathways contribute to redox homeostasis by regulating ROS generation via NOX/NADPH and mitochondrial ETC as well as by their impact on antioxidant systems via production of NADPH and GSH, as outlined in Figure 3. Conversely, cytosolic and mitoROS, which are produced by NOX, mitochondrial respiration, as well as metabolic and other enzymes, regulate metabolic pathways by targeting specific enzymes and transcription factors, including AMPK, glycolytic enzymes, mitochondrial enzymes, and HIFs. HIF-1α promotes a shift in metabolism toward glycolysis, while inhibiting mitochondrial O2 consumption. This leads to decreased production of ATP through oxidative phosphorylation and thus reduced levels of mitoROS. AMPK, 5′ adenosine monophosphate-activated protein kinase; HIF, hypoxia-inducible factor; O2, oxygen. Color images are available online.
FIG. 6.
FIG. 6.
The interplay between metabolic pathways and ROS (redox homeostasis) in physiological and pathological states.Left panel, glycolysis plays an essential role in the control of redox homeostasis by generating PPP-derived NADPH that is involved in the antioxidant system. FAO also generates NADPH through metabolic reactions. Glutaminolysis is involved in redox control by increasing GSH synthesis. During mitochondrial metabolism, ROS will be produced via ETC. NO• is produced by NOS by utilizing BH4, NADPH, and molecular O2 to convert l-arginine to l-citrulline (coupled eNOS). NOXs- and mitochondria-derived ROS activate redox signaling. Right panel, in pathological states such as diabetes and atherosclerosis, excess ROS due to eNOS uncoupling and PPP-GSH impairment inhibit glycolytic flux, which diverts glycolytic intermediates into alternative metabolic pathways such as polyol pathway (AGE production) and PKC activation. This, in turn, further increases mitochondria- or NOX-derived ROS production and mitochondrial dysfunction. mitoROS or Nox-derived ROS stabilize HIF-1α, which induces a metabolic shift toward glycolysis, resulting in reduced oxidative phosphorylation and mitoROS production. The ADMA produced by l-arginine methylation via the 1C metabolism as well as arginase inhibit l-arginine binding to NOS, which decreases NO production. The mevalonate pathway also facilitates eNOS uncoupling by RhoAprenylation induced by GGPP, thereby promoting excess ROS production. ADMA, asymmetric dimethylarginine; GGPP, geranylgeranyl pyrophosphate; PKC, protein kinase C. Color images are available online.
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