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

Area of Science:

• Reproductive biology
• Mitochondrial genetics
• Epigenetics

Background:

• Mitochondria are crucial for female reproduction, but the impact of mitochondrial DNA (mtDNA) mutations in oocytes is not well understood.
• Oocyte quality is critical for successful embryonic development and epigenetic reprogramming.

Purpose of the Study:

• To investigate the role of oocyte mitochondrial DNA (mtDNA) mutations in early embryonic development and epigenetic reprogramming.
• To identify potential therapeutic targets for fertility decline associated with mitochondrial dysfunction.

Main Methods:

• Utilized a mouse model with a mitochondrial DNA mutator (Polg^m) to study oocyte mtDNA mutation effects.
• Performed spindle-chromosome exchange experiments to assess cytoplasmic factors.
• Conducted metabolomic profiling and analyzed DNA methylation and gene expression in embryos.

Main Results:

• Embryos from Polg^m oocytes exhibited fetal growth retardation and placental dysfunction.
• Polg^m oocytes showed global DNA hypomethylation, leading to insufficient zygotic genome demethylation and gene expression dysregulation.
• Reduced α-ketoglutarate (αKG) levels were observed in Polg^m oocytes; αKG supplementation rescued epigenetic defects and developmental issues.

Conclusions:

• Oocyte mtDNA mutations significantly impair embryonic development by disrupting epigenetic reprogramming.
• α-ketoglutarate (αKG) plays a vital role in maintaining oocyte epigenetic integrity and embryonic development.
• αKG supplementation holds potential for treating infertility linked to mitochondrial dysfunction.