# Identification Exploring the Mechanism and Clinical Validation of Mitochondrial Dynamics-Related Genes in Membranous Nephropathy Based on Mendelian Randomization Study and Bioinformatics Analysis

## TL;DR

This study explores how mitochondrial dynamics-related genes contribute to membranous nephropathy, identifying key genes and immune cell changes that could lead to new diagnostic and treatment approaches.

## Contribution

The study identifies four key mitochondrial dynamics-related genes and their roles in membranous nephropathy through multi-omics and clinical validation.

## Key findings

- Four key MDGs (RTTN, MYO9A, USP40, NFKBIZ) were identified as critical in membranous nephropathy.
- A nomogram model achieved perfect diagnostic performance (AUC = 1) using these genes.
- RT-qPCR confirmed significant downregulation of the four genes in MN samples.

## Abstract

Background: Membranous nephropathy (MN), a prevalent glomerular disorder, remains poorly understood in terms of its association with mitochondrial dynamics (MD). This study investigated the mechanistic involvement of mitochondrial dynamics-related genes (MDGs) in the pathogenesis of MN. Methods: Comprehensive bioinformatics analyses—encompassing Mendelian randomization, machine-learning algorithms, and single-cell RNA sequencing (scRNA-seq)—were employed to interrogate transcriptomic datasets (GSE200828, GSE73953, and GSE241302). Core MDGs were further validated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Results: Four key MDGs—RTTN, MYO9A, USP40, and NFKBIZ—emerged as critical determinants, predominantly enriched in olfactory transduction pathways. A nomogram model exhibited exceptional diagnostic performance (area under the curve [AUC] = 1). Seventeen immune cell subsets, including regulatory T cells and activated dendritic cells, demonstrated significant differential infiltration in MN. Regulatory network analyses revealed ATF2 co-regulation mediated by RTTN and MYO9A, along with RTTN-driven modulation of ELOA-AS1 via hsa-mir-431-5p. scRNA-seq analysis identified mesenchymal–epithelial transitioning cells as key contributors, with pseudotime trajectory mapping indicating distinct temporal expression profiles: NFKBIZ (initial upregulation followed by decline), USP40 (gradual fluctuation), and RTTN (persistently low expression). RT-qPCR results corroborated a significant downregulation of all four genes in MN samples compared to controls (p < 0.05). Conclusions: These findings elucidate the molecular underpinnings of MDG-mediated mechanisms in MN, revealing novel diagnostic biomarkers and therapeutic targets. The data underscore the interplay between mitochondrial dynamics and immune dysregulation in MN progression, providing a foundation for precision medicine strategies.