Causal Effects of Mitochondrial Proteins on Primary Ovarian Insufficiency Risk: A Mendelian Randomization Study

Background: Primary ovarian insufficiency (POI), characterized by infertility and an elevated risk of multiple comorbidities, affects approximately 1% of women <40 years of age. Although mitochondrial dysfunction has been associated with POI, the specific mitochondrial proteins involved in its pathogenesis remain largely unidentified. To address this gap, the present study investigated the causal relationship between mitochondrial proteins and POI using a bidirectional Mendelian randomization (MR) approach. Methods: Bidirectional MR analysis was conducted using genetic data derived from the INTERVAL and FinnGen databases. Plasma data for 3622 proteins, including 66 mitochondrial proteins, were examined. Genetic instruments were selected based on a stringent genome-wide significance threshold, and causal associations were estimated using the inverse-variance weighted method. Results: The analysis revealed that higher levels of 39S ribosomal protein L14 (odds ratio [OR] = 0.40, p = 0.009), oligoribonuclease (OR = 0.64, p = 0.031), and mitochondrial fission regulator 1 (OR = 0.60, p = 0.044) were significantly associated with a reduced risk POI. In contrast, higher levels of coiled-coil domain-containing protein 90B were associated with an increased risk of POI (OR = 1.80, p = 0.042). Conclusions: This study identified key mitochondrial proteins associated with a reduced risk of POI, highlighting the potential role of mitochondrial pathways in POI pathogenesis and offering possible targets for future diagnostic and therapeutic interventions.