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Mitochondrial haplotype influences ovarian aging in genetically heterogeneous rats

ABSTRACT: Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose to age-associated comorbidities. Despite these clinical implications, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it has not been established experimentally whether mitochondrial genetic diversity itself is a determinant of ovarian aging trajectories. To address this, we developed two genetically heterogeneous rat cohorts (OKC-HETB and OKC-HETW) that differ in mitochondrial haplotype while maintaining nuclear genome diversity. Our findings reveal that the OKC-HETW haplotype results in an accelerated loss of primordial follicle reserve and pathological stroma remodeling marked by fibrosis, macrophage infiltration, and the accumulation of multinucleated giant cells (MNGCs). 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE328056 | GEO | 2026/09/17

REPOSITORIES: GEO

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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Mitochondrial haplotype influences ovarian aging in genetically heterogeneous rats

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