Metabolic Plasticity and Transcriptomic Reprogramming Orchestrate Hypoxia Adaptation in Yak.

The yak () has exceptional hypoxia resilience, making it an ideal model for studying high-altitude adaptation. Here, we investigated the effects of oxygen concentration on yak cardiac fibroblast proliferation and the underlying molecular regulatory pathways using RNA sequencing (RNA-seq) and metabolic analyses. Decreased oxygen levels significantly inhibited cardiac fibroblast proliferation and activity. Intriguingly, while the mitochondrial DNA (mtDNA) content remained stable, we observed coordinated upregulation of mtDNA-encoded oxidative phosphorylation components. Live-cell metabolic assessment further demonstrated that hypoxia led to mitochondrial respiratory inhibition and enhanced glycolysis. RNA-seq analysis identified key hypoxia adaptation genes, including glycolysis regulators (e.g., , ), and hypoxia-inducible factor 1-alpha (), with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighting their involvement in metabolic regulation. The protein-protein interaction network identified three consensus hub genes across five topological algorithms (, , and ) that may be involved in hypoxia adaptation. These findings highlight the importance of metabolic reprogramming underlying yak adaptation to hypoxia, providing valuable molecular insights into the mechanisms underlying high-altitude survival.