Glutathione decline coordinates mitochondria to license histone acetylation and zygotic genome activation

The glutathione (GSH) metabolism pathway plays a pivotal role in maintaining redox homeostasis, yet its coordination with mitochondrial function and Reactive Oxygen Species (ROS) dynamics during this process remains poorly defined. Here, we report that a developmentally programmed decline in endogenous GSH occurs from the zygote to the 2-cell stage, while ROS levels and mitochondrial activity remain low. Perturbation of this physiological GSH decrease-either by depletion or excessive supplementation-led to developmental arrest at the 2-cell stage, accompanied by aberrant histone acetylation, premature elevation of mitochondrial activity. Further examination revealed these interferences downregulated key zygotic genome activation (ZGA) transcription factors and mitochondrial genes. Furthermore, we show that Antioxidants such as GSH, α-lipoic acid, and vitamin C can partially rescue embryonic defects induced by redox imbalance, albeit with varying efficacy. Our findings uncover GSH-mediated redox balance in regulating histone acetylation and mitochondrial maturation from the zygote to 2-cell stages, providing new insights into the metabolic-epigenetic interplay that guides early embryogenesis.