Distinct causal associations of mitochondrial function-related proteins with eclampsia versus pre-eclampsia: a two-sample Mendelian randomization analysis

Objective Eclampsia (E) and pre-eclampsia (PE) exhibit significant pathophysiological differences, yet the mitochondrial mechanisms underlying these differences are unclear. Our study conducted the first Mendelian randomization (MR) analysis to explore the specific causal effects of mitochondrial function-related proteins on E and PE, identifying actionable targets for precise prevention.Methods This two-sample Mendelian randomization study utilized three European-ancestry cohorts from FinnGen R12 (E/PE, E, and PE). Causal effects of mitochondrial proteins were estimated via the inverse variance weighted (IVW) method, with robustness confirmed through sensitivity analyses and MR-PRESSO for outlier removal. For mitochondrial genes identified through correction methods, we further conducted transcriptomic validation using independent GEO datasets to identify disease-causing genes associated with E/PE.Results The IVW results revealed distinct causal associations for E and PE. Specifically, 2,4-dienoyl-CoA reductase (DECR1) was associated with an increased risk of E (OR = 1.8788, 95% CI 1.0446–3.3791, p = 0.0352), while Serine-tRNA ligase (SerRS) showed a protective association with E (OR = 0.3090, 95% CI 0.1346–0.7097, p = 0.0056). For pre-eclampsia, Persulfide dioxygenase ETHE1 was associated with decreased risk (OR = 0.9341, 95% CI 0.8762–0.9958, p = 0.0367), while Transmembrane protein 70 (TMEM70) was associated with increased risk (OR = 1.0937, 95% CI 1.0023–1.1935, p = 0.0442). External validation using GEO datasets showed differential expression patterns of these genes in PE placental tissues.Conclusion This MR study suggests distinct mitochondrial pathways for E and PE, with DECR1 and SerRS associated with E, and ETHE1 and TMEM70 with PE. These preliminary findings suggest non-overlapping genetic underpinnings and highlight the proteins as potential biomarkers for further investigation.