Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases

Abstract

Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung-gut, lung-brain, and brain-gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut-lung-brain axis may play a key role in metabolic reprogramming.

Keywords: Bronchopulmonary dysplasia; Hyperoxia; Metabolic reprogramming; Mitochondria; Neonate.

Fig. 1

Catabolism of glucose, fatty acid, and amino acids. Glucose enters the cell through glucose transporters and is phosphorylated by hexokinase2 (HK2) to form glucose-6-phosphate (G6P). G6P is metabolized by glycolysis and the pentose phosphate pathway (PPP), then isomerized into fructose-6-phosphate and metabolized by various glycolytic enzymes into pyruvate, which enters the mitochondria for the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. The uptake of exogenous fatty acids requires specialized transporters to facilitate effective transmembrane transfer, including CD36. The uptake of exogenous fatty acids increases; these are stored in lipid droplets. Fatty acids are degraded by oxidation to produce acyl-CoA. Acyl-CoA then enters the TCA cycle to supply NADH and FADH2 to the electron transport chain. De novo lipid synthesis describes the process of converting carbohydrates (such as glucose) and amino acids (including glutamine) to fatty acids. The catabolism of amino acids includes deamination and decarboxylation. Glutamine is the most abundant free amino acid, which enters the cytoplasm via the solute carrier family 1 member 5(SLC1A5) or alanine-serine-cysteine transporter 2 (ASCT2), and is catalyzed by glutaminase to glutamate. Glutamate can be transferred into the mitochondria and converted to alpha-ketoglutaric acid by oxidative deamination of glutamate dehydrogenase 1 (GLUD1), which is utilized as a TCA cycle intermediate for energy recycling in the mitochondrion. Image generated using Bio-Render software.

Fig. 2

Metabolic dysregulation in hyperoxia-associated neonatal diseases. In the glucose metabolism of bronchopulmonary dysplasia (BPD), glycolysis, PPP, and urine lactate are increased, whereas in the TCA cycle, oxygen consumption rates, complex I, complex II, and urine gluconate are decreased. In the lipid metabolism of BPD, β-oxidation, carnitines, linoleic acid (LA), fatty acid binding protein 4 (FABP4), sphingolipids, unsaturated hydroxy fatty acids, oxy fatty acids, sulfated steroid, glycerophospholipid, and glycerolipid are increased, whereas docosahexaenoic acid, dipalmitoyl lecithin, adiponectin, and Cpt1a are decreased. In the amino acid metabolism of BPD, phenylalanine, histidine, asparagine, glycine, and isoleucine are increased, whereas alanine, tyrosine, threonine, arginine, glutamine, S-adenosyl methionine, l-citrulline, and l-arginine are decreased. In the glucose metabolism of BPD-associated pulmonary hypertension (PH), G6P, phosphoenolpyruvate, and glycogen synthase kinase-3b (GSK-3b) are increased, whereas guanylate cyclase and cGMP are decreased. In the lipid metabolism of BPD-associated PH, nonadecanoic acid and oxylipin are increased, whereas phosphatidylcholines, sphingomyelins, cholesterol esters, lysophosphatidylcholines, triacylglycerides, plasmalogen-phosphatidylcholines, and plasmalogen-phosphatidylethanolamines are decreased. In the amino acid metabolism of BPD-associated PH, asparagine and creatinine are increased, whereas lysine, ornithine, phenylalanine, arginine, and citrulline are decreased. In the glucose metabolism of hyperoxia-associated brain injury, glycolysis, G6P, and PPP are increased, whereas glucose metabolism and the TCA cycle are decreased. In the amino acid metabolism of hyperoxia-associated brain injury, glutamate, excitatory amino acid transporter (EAAT) 1, 2, and 3, and vesicular glutamate transporter (VGLUT) 1 and 2 are increased. In the glucose metabolism of hyperoxia-associated gut injury, lactate dehydrogenase (LDH) is increased. In the lipid metabolism of hyperoxia-associated gut injury, the intestinal fatty acid binding protein (i-FABP) is increased. In the amino acid metabolism of hyperoxia-associated gut injury, arginine and glutamine are decreased. In the glucose metabolism of retinopathy of prematurity (ROP), glycolysis, lactate, and pyruvate are increased, whereas citrate, aconitate, and succinyl carnitine are decreased. In the lipid metabolism of ROP, arachidonic acid and short- and long-chain fatty acids are decreased. In the amino acid metabolism of ROP, glycine is increased. Hyperoxia also causes heart, liver, and kidney injury by metabolic reprogramming, although few studies have analyzed this mechanism. Image generated using Bio-Render software.

Fig. 3

Potential role of mitochondria in the metabolic reprogramming of hyperoxia-induced neonatal diseases. Hyperoxia increases the formation of mtROS, which can upregulate the expression of HIF-1α, which then regulates glucose metabolic reprogramming such as glucose transporters (GLUT1 and GLUT3), glycolytic enzymes (e.g., HK1, HK2, Eno1, PKM2), and lactate dehydrogenase (LDH). mtROS can also activate NOX1, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-κB (NF- κB), silent information regulator family protein 1 (Sirt1), and tumor necrosis factor (TNF) pathways. In addition, mtROS can directly interact with the enzymes of glycolysis, such as HK2, PDH, and α-KGDH, the enzymes of lipid metabolism, such as hydroxymethylglutaryl (HMG)-CoA and fatty acid synthase (FAS), and the enzymes of amino acid metabolism, such as glutamate dehydrogenase (GDH) and aspartate aminotransferase (AST). Hyperoxia will also change mitochondria dynamics; that is, mitochondrial fusion is reduced, whereas mitochondrial fission and mitophagy are enhanced. Image generated using Bio-Render software.

Fig. 4

Potential role of the gut–lung–brain axis in the metabolic reprogramming of hyperoxia-induced neonatal diseases. Hyperoxia can cause multiple-organ injury in neonates, including in the brain, lung, and gut. As well as direct damage, hyperoxia is also associated with the interaction between organs. Hyperoxia can activate the gut–lung axis, lung–brain axis, and gut–brain axis. Therefore, we suggest that a “gut–lung–brain” axis exists in neonatal oxidative stress diseases. Image generated using Bio-Render software.