Mitofusin 1 Drives Preimplantation Development by Enhancing Chromatin Incorporation of Histone H3.3

Abstract Mitofusin 1 (MFN1) plays a crucial role in mitochondrial fusion and oocyte development. However, its function in preimplantation embryonic development and its potential involvement in epigenetic regulation remain poorly understood. In this study, it is shown that MFN1 interacts with PADI6, a key component of the cytoplasmic lattice in oocytes and early embryos. MFN1 deficiency in mice results in reduced PADI6 levels and decreased expression of translational machinery components, which suppress protein synthesis activity and lower histone H3.3 abundance. These disruptions lead to the failure of male pronucleus formation, aberrant zygotic genome activation, and impaired embryonic development. It is further demonstrated that the MFN1 activator S89 promotes H3.3 incorporation and rescues early development in maternally aged embryos with low MFN1 levels. Additionally, a positive correlation between MFN1 and H3.3 protein levels in early human embryos is observed. Together, these findings provide new insights into MFN1's role in regulating epigenetic reprogramming during preimplantation embryo development.