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Spatio-temporal analysis deciphers the energy metabolism disorders in depression based on stable isotope-resolved metabolomics

ABSTRACT: The severe harm of depression on human life has attracted great attention. However, due to its unclear and extremely complex pathogenesis, the efficacy of existing marketed antidepressants is far from satisfactory. Consequently, it is urgent to understand the pathogenesis of depression from novel perspectives and develop next-generation antidepressants targeting innovative mechanisms. In recent years, the hypothesis of energy metabolism disorders in depression has emerged as a groundbreaking research direction. Here, we provided a new strategy for deciphering energy metabolism disorders in depression through spatio-temporal analysis based on stable isotope-resolved metabolomics. We used the classic depression model—chronic unpredictable mild stress (CUMS) rats—as the experimental subjects and the nephrotic syndrome (NS) rat model, which also exhibits energy metabolism abnormalities, as the comparison object. Sable isotope tracing technology and the pseudo-first-order kinetics mathematical model were introduced to evaluate the metabolic rates and the isotope distribution across various tissues from spatio-temporal dimension. Our findings revealed that CUMS rats exhibited impaired TCA cycle activity and activated gluconeogenesis, whereas NS rats showed impaired TCA cycle and enhanced fatty acid β-oxidation. In addition, our results showed an interesting phenomenon that caecum had the lowest abundances in all metabolic pathways, while serum, brain and heart, brain, brain, kidney displayed the highest abundances in glycolysis/gluconeogenesis, TCA cycle, neurotransmitters metabolism, amino acids metabolism, fatty acids metabolism, respectively. The results comprehensively and accurately revealed the specific pathway of energy metabolism disorders in depression from spatio-temporal perspective. Our study provided a novel insight for exploring the pathological mechanisms of depression, identifying new therapeutic targets, and developing ideal antidepressants.

ORGANISM(S): Rattus Rattus

SUBMITTER: Ruiping Zhang

PROVIDER: PXD066143 | iProX | Mon Jul 14 00:00:00 BST 2025

REPOSITORIES: iProX

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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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Spatio-temporal analysis deciphers the energy metabolism disorders in depression based on stable isotope-resolved metabolomics

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