Mitochondrial haplotype influences ovarian aging in genetically heterogeneous rats

These tissue-level pathologies were preceded by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM protein levels were elevated, OKC-HETW ovaries showed reduced TFAM-mtDNA binding and suppressed TOMM20 abundance, implying that impaired TOMM20-mediated import leads to compromised mitochondrial genomic stability.

Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype determines the rate of molecular aging, as OKC-HETW ovaries experience accelerated age-dependent activation of inflammatory and fibrotic pathways alongside suppression of proteostasis and mitochondrial function. These mitochondrial and molecular defects translated to reduced ovulation rates and impaired oocyte quality. Taken together, our findings pinpoint mitochondrial genetics as a key regulator of ovarian aging and putative target to preserve ovarian function and female healthspan.