Maternal <scp>LDHB</scp> Safeguards Redox Balance and Developmental Competence During Preimplantation Embryo Cleavage

The metabolic regulation in embryos is distinct from that in somatic cells. Early mammalian embryos obtain nutrients from the maternal environment to fulfill the energy requirements of growth and development, and lactate is one of the major substrates of embryonic energy metabolism. To interrogate metabolic regulation during early embryogenesis, we transiently inhibited maternally supplied Lactate dehydrogenase B (LDHB) in early embryos, and found that inhibition led to developmental arrest during the 4- to 8-cell transition, reduced ATP levels, impaired mitochondrial readouts and a decreased NAD+/NADH ratio. Aspartate supplementation rescued developmental progression and restored the NAD+/NADH balance in a malate-aspartate shuttle (MAS)-dependent manner. Together, these data suggest that maternal LDHB is important during the 4- to 8-cell transition to maintain LDH-linked redox homeostasis, and that MAS activity contributes to redox restoration during the rescue. Our study highlights a link between metabolic flexibility, redox homeostasis, and developmental competence during mammalian preimplantation development.