Identification and validation of mitochondria-associated endoplasmic reticulum membrane-associated genes as diagnostic biomarkers for preeclampsia

Abstract

Background ER-mitochondria Ca2+ transfer abnormalities by MAMs and subsequent resulting in mitochondrial autophagy contribute to trophoblast apoptosis and may be involved in the pathogenesis of PE suggesting a crucial role of MAMs in PE development. However, detailed investigations into the specific mechanisms and roles of MAMs in PE remain limited. Methods This study began with a search for PE-related datasets and MAMs-related genes. Candidate genes identified and analyzed by differential expression analysis and WGCNA. ROC analysis was conducted to evaluate the capacity of biomarkers to differentiate between PE and controls. GSEA was employed to understand the biological functions and immunoinfiltration analysis was utilized for revealing role of the immmunological system of biomarkers in the advancement of PE. Biomarker-disease association predicting and constructing of molecular regulatory networks were implemented to explore the mechanisms by which biomarkers affect PE. Expression of hub genes was further verified by RT-qPCR. Results ABCD3, CAST and PAWR were considered as latent diagnostic biomarkers for PE, and the AUCs representing the ability to diagnose PE were 0.8-1.0.GSEA found spliceosome, proteasome and ubiquitin-mediated proteolysis were co-enriched by biomarkers. Immunoinfiltration analysis certified negative correlations between biomarkers and differentially infiltrated immune cells. Using the NetworkAnalyst database, 21, 9 and 20 TFs that might regulate the level of ABCD3, CAST and PAWR. RT-qPCR verified down-regulation of CAST and PAWR in the PE placenta, but ABCD3 validation results was the opposite. Conclusion CAST and PAWR function as latent MAMs-related biomarkers diagnosing and affecting PE. These findings provided insights to enhance the diagnosis and treatment of PE.