The mitochondria-mediated regulation network on cellular oxygen metabolism capacity revealed by bovine cybrids model

Emerging evidence suggests that mitochondrial-nuclear genomic crosstalk plays a role in phenotypic regulation. However, the molecular mechanisms underlying functional gene coordination and the dynamics of regulatory networks remain incompletely characterized. In the present study, we established bovine cybrid models harboring isogenic nuclear genomes but distinct mitochondria adapted to different environmental oxygen tensions. Multi-omics analyses identified 437 DEmRNAs, 48 DElncRNAs, 169 DEcircRNAs, 154 DEmiRNAs, and 91 DEPs between the isonuclear cybrids with different mitochondrial backgrounds. Reconstruction of the regulatory network elucidated two ceRNA networks consisting of 112 mRNAs, 11 miRNAs, and 21 lncRNAs. Cross-omics integrative analysis revealed 37 concordantly regulated targets that exhibited significant expression alterations at both transcriptional and translational levels, including DSG3, DSC2, ISG15, and IGFBP2. Functional enrichment analysis indicated that these molecular determinants were critically involved in steroid biosynthetic processes, cGMP-PKG signal transduction, and NLR-mediated inflammatory responses. Collectively, our findings demonstrate that mitogenomes orchestrate cellular energy homeostasis and hypoxic adaptation through synergistic regulation of nuclear gene expression and post-translational modifications.