Mitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes

The efficacy of assisted reproductive technologies (ARTs) in older women remains constrained, largely due to an incomplete understanding of the underlying pathophysiology. This review aims to consolidate the current knowledge on age-associated mitochondrial alterations and their implications for ovarian aging, with an emphasis on the causes of mitochondrial DNA (mtDNA) mutations, their repair mechanisms, and future therapeutic directions. Relevant articles published up to 30 September 2024 were identified through a systematic search of electronic databases. The free radical theory proposes that reactive oxygen species (ROS) inflict damage on mtDNA and impair mitochondrial function essential for ATP generation in oocytes. Oocytes face prolonged pressure to repair mtDNA mutations, persisting for up to five decades. MtDNA exhibits limited capacity for double-strand break repair, heavily depending on poly ADP-ribose polymerase 1 (PARP1)-mediated repair of single-strand breaks. This process depletes nicotinamide adenine dinucleotide (NAD⁺) and ATP, creating a detrimental cycle where continued mtDNA repair further compromises oocyte functionality. Interventions that interrupt this destructive cycle may offer preventive benefits. In conclusion, the cumulative burden of mtDNA mutations and repair demands can lead to ATP depletion and elevate the risk of aneuploidy, ultimately contributing to ART failure in older women.