Lactate deficiency-induced early embryonic arrest is mitigated through malate-aspartate shuttle

During assisted reproductive technology (ART) procedure, approximately one third to half of the in vitro fertilization (IVF) derived embryos cannot reach the blastocyst stage, and about 10% arrest at the early cleavage stage. Early mammalian embryos obtain nutrients from maternal environment to fulfill the energy requirements of growth and development, and lactate is one of the major substrates of embryo energy metabolism. To explicitly reveal the energy metabolism in early embryogenesis, we inhibited the production and uptake of lactate at the zygote stage, and found it resulted developmental arrest, impaired mitochondrial activity and reduced NAD+/NADH ratio. By activating the malate-aspartate shuttle (MAS), the developmental arrest was rescued through the restoration of NAD+/NADH balance. Therefore, we demonstrate that maternal LDHB plays an essential role from 4- to 8-cell stage that it converts lactate from pyruvate to generate NAD+, and MAS activation is responsible for the re-equilibrium of NAD+/NADH. Our study discusses the association of metabolic flexibility and developmental regulation, and deepens our understanding of the metabolic mechanism of embryonic development. For single-cell transcriptome sequencing, six 4-cell mouse embryos were collected from each untreated (control) and LDHB inhibition group, with three replicates for each group.