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Zakhartsev2022 - Constraint-based model of metabolism of Atlantic salmon (Salmo salar)

ABSTRACT: SALARECON links the Atlantic salmon genome to metabolic fluxes and growth, focusing on energy, amino acid, and nucleotide metabolism.

SUBMITTER: Jon Olav Vik

PROVIDER: MODEL2207070001 | BioModels | 2023-01-11

REPOSITORIES: BioModels

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Project description:Exposure to hypoxia disrupts energy metabolism and induces inflammation. However, the pathways and mechanisms underlying energy metabolism disorders caused by hypoxic conditions remain unclear. In this study, we constructed a hypoxic animal model and applied transcriptomic and non-targeted metabolomics techniques to further investigate the pathways and mechanisms of hypoxia exposure that disrupt energy metabolism. Transcriptome results showed that 3007 genes were significantly differentially expressed under hypoxic exposure, and Gene Ontology (GO) annotation analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes (DEGs) were mainly involved in energy metabolism and were significantly enriched in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathway. Differential genes in the TCA cycle (IDH3A, SUCLA2, and MDH2) and OXPHOS pathway (NDUFA3, NDUFS7, UQCRC1, CYC1, and UQCRFS1) were validated using mRNA and protein expression, and the results showed downregulation. The results of non-targeted metabolomics showed that 365 significant differential metabolites were identified under plateau hypoxia stress. KEGG enrichment analysis showed that the differential metabolites were mainly enriched in metabolic processes, such as energy metabolism, nucleotide metabolism, and amino acid metabolism. Hypoxia exposure disrupted the TCA cycle and reduced the synthesis of amino acids and nucleotides by decreasing the concentrations of cis-aconitate, α-ketoglutarate, NADH, NADPH, most amino acids, purines, and pyrimidines. Bioinformatics analysis was used to identify inflammatory genes related to hypoxia exposure, and some inflammatory genes were selected for verification. We found that the mRNA and protein expression levels of IL1B, IL12B, S100A8, and S100A9 in kidney tissues were upregulated under hypoxic exposure. Our results suggest that hypoxia exposure inhibits the TCA cycle and OXPHOS signalling pathway by inhibiting IDH3A, SUCLA2, MDH2, NDUFFA3, NDUFS7, UQCRC1, CYC1, and UQCRFS1, thereby suppressing energy metabolism, inducing amino acid and nucleotide deficiency, and promoting inflammation, ultimately leading to kidney damage.

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Zakhartsev2022 - Constraint-based model of metabolism of Atlantic salmon (Salmo salar)

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