Regulation of α-Ketoglutarate levels by Myc affects metabolism and demethylation in porcine early embryos

The <i>Myc</i> family is essential for cell proliferation, differentiation, and metabolism, particularly in embryonic development and stem cell functions. However, the specific role of <i>Myc</i> in porcine early embryonic development is not fully understood. This study observed high <i>Myc</i> expression during the four-cell stage of porcine embryos. Inhibition of <i>Myc</i> using 10058-F4 impaired embryonic development, disrupted energy metabolism, and increased DNA methylation. Mechanistically, these effects were dependent on α-KG, a TCA cycle intermediate and cofactor for TET demethylation enzymes. Sequencing analysis of four-cell embryos post-<i>Myc</i> inhibition revealed downregulation of key metabolic enzymes related to α-KG, such as CS, IDH2, leading to reduced α-KG levels. Supplementation with α-Ketoglutarate (α-KG) mitigated the negative effects of <i>Myc</i> inhibition, including lower blastocyst rates, decreased ATP levels, and increased 5 mC levels. In conclusion, <i>Myc</i> regulates the expression of key metabolic enzymes during the four-cell stage, influencing early embryonic metabolism and epigenetic reprogramming.