Increased mtDNA mutation frequency in oocytes causes epigenetic alterations and embryonic defects.

Mitochondria are essential for female reproductive processes, yet the function of mitochondrial DNA (mtDNA) mutation in oocytes remains elusive. By employing an mtDNA mutator (Polg m ) mouse model, we found the fetal growth retardation and placental dysfunction in post-implantation embryos derived from Polg m oocytes. Remarkably, Polg m oocytes displayed the global loss of DNA methylation; following fertilization, zygotic genome experienced insufficient demethylation, along with dysregulation of gene expression. Spindle-chromosome exchange experiment revealed that cytoplasmic factors in Polg m oocytes are responsible for such a deficient epigenetic remodeling. Moreover, metabolomic profiling identified a significant reduction in the α-ketoglutarate (αKG) level in oocytes from Polg m mice. Importantly, αKG supplement restored both DNA methylation state and transcriptional activity in Polg m embryos, consequently preventing the developmental defects. Our findings uncover the important role of oocyte mtDNA mutation in controlling epigenetic reprogramming and gene expression during embryogenesis. αKG deserves further evaluation as a potential drug for treating mitochondrial dysfunction-related fertility decline.