August 14, 2025Open Access

Stress-Induced Altered Expression of Hippocampal Nuclear and Mitochondrial Encoded Genes in Rats and Cross-Species Genetic Associations Reveal Molecular Links to Depression

EHEllie Marie HulwiUniversity of Alabama at Birmingham QWQingzhong WangQilu University of Technology AFAleena FrancisUniversity of Alabama at Birmingham

Key Points

Restraint stress significantly impacts mitochondrial functions and alters gene expression associated with depression.
Key findings reveal 39 SNPs related to the depression phenotype, with rs10899570 being highly significant.
Analysis utilized WGCNA to identify functional modules connected to the restraint phenotype, indicating neural plasticity impairment.
The research highlights crucial molecular links between mitochondrial dysfunction and depression, suggesting targets for intervention.

Abstract

Abstract Background Mitochondria play a pivotal role in energy production, and their dysfunction not only hampers cells' ability to meet energy requirements but also contributes to the impairment of neural plasticity, a critical feature of depressive disorders. In this study, mitochondrial cross-omics analysis was carried out in the hippocampus of restraint rats to understand the role of mitochondria in depression pathophysiology. Methods The expression profiles of hippocampal mitochondrial and nuclear-encoded genes in mitochondrial fractions from restraint and handled control rats were obtained using high-throughput RNA sequencing. WGCNA was used to identify the gene co-expression and pathways associated with the restraint phenotype. Mutual Information Network algorithm tools Arance, CLR, and MRNET were additionally used to screen the functional modules and hub genes and their similarity with the WGCNA-based network analysis. Finally, cross-species homology followed by gene association analysis was conducted to obtain SNPs and haplotypes related to depression phenotype. Results A significant proportion of mitochondrial and nuclear-encoded genes showed differential regulation in the hippocampus of restraint rats. WGCNA and Mutual Information Network analysis yielded distinct functional modules significantly related to restraint phenotype. Further network analysis revealed distinct co-expression patterns associated with differentially expressed genes associated with these modules. Cross-species analysis showed 39 significantly associated SNPs with the depression phenotype, where the most significant SNP, rs10899570, was located within the TENM4 gene. Further, rs1573529 and rs10899570 were distributed into the linkage disequilibrium block where SNPs were highly correlated. Subsequent haplotype analysis showed that rs1573529 and rs10899570 were significantly associated with depressive behavior. Conclusions The study demonstrates a significant impact of restraint stress on mitochondrial functions and genetic association, suggesting their critical role in depression pathophysiology.

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