Lactate metabolism inhibition disrupts goat oocyte meiosis via H3K18la-mediated epigenetic dysregulation

Lactylation, a newly discovered histone post-translational modification, has emerged as a key metabolic-epigenetic regulator; however, its dynamic functions during oocyte maturation remain unexplored. This study demonstrates that pharmacological inhibition of lactate metabolism by GNE-140 (a Lactate Dehydrogenase Inhibitor) and 2-deoxy-D-glucose (2-DG, a glycolysis inhibitor) significantly compromises the quality of goat oocytes. These inhibitors disrupt meiotic progression and impair developmental competence by perturbing spindle assembly, actin Cytoskeleton dynamics, and chromosomal alignment, ultimately leading to maturation arrest. In addition, metabolic inhibition induces pronounced mitochondrial dysfunction, characterized by elevated levels of Reactive Oxygen Species (ROS), increased DNA damage, and Apoptosis. Functionally, oocytes exposed to these metabolic inhibitors exhibit markedly reduced fertilization rates and diminished blastocyst formation potential, highlighting the long-term developmental consequences of impaired lactate metabolism. To elucidate the underlying mechanisms, we integrated transcriptomic analysis (RNA-seq) with chromatin profiling (CUT&Tag for H3K18la), which revealed ribosomal protein L8 (RPL8) as a potential downstream effector. Pathway enrichment analysis further implicated disruptions in Oxidative Phosphorylation, lactate metabolism, and gene networks associated with oocyte meiosis. Collectively, our findings uncover a novel mechanistic link between metabolic regulation, epigenetic modification, and oocyte maturation, providing valuable insights for optimizing in vitro maturation protocols in caprine species and potentially Other mammals.

Goat oocyte maturation; H3K18la; Histone lactylation; Mitochondria.