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Identification Exploring the Mechanism and Clinical Validation of Mitochondrial Dynamics-Related Genes in Membranous
Qiuyuan Shao1, Nan Li1, Huimin Qiu1
1Department of Nephrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210023, China.
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.
Insights
Mitochondrial dynamics genes (MDGs) like RTTN, MYO9A, USP40, and NFKBIZ are significantly downregulated in membranous nephropathy (MN), offering new diagnostic and therapeutic avenues for this kidney disorder.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Membranous nephropathy (MN) is a common glomerular disease with unclear mechanisms.
- The role of mitochondrial dynamics (MD) and related genes (MDGs) in MN pathogenesis is largely unknown.
Purpose of the Study:
- To investigate the mechanistic involvement of MDGs in MN pathogenesis.
- To identify potential diagnostic biomarkers and therapeutic targets for MN.
Main Methods:
- Bioinformatics analyses including Mendelian randomization and machine learning on transcriptomic datasets.
- Single-cell RNA sequencing (scRNA-seq) for cellular and temporal profiling.
- Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for gene validation.
Main Results:
- Four core MDGs (RTTN, MYO9A, USP40, NFKBIZ) were identified as critical determinants in MN.
- A nomogram model showed perfect diagnostic performance (AUC=1).
- Significant immune cell infiltration and regulatory network alterations were observed, with MDGs downregulated in MN patients.
Conclusions:
- MDGs play a crucial role in MN pathogenesis, linked to immune dysregulation.
- Identified MDGs and pathways represent novel diagnostic biomarkers and therapeutic targets for MN.
- Findings support precision medicine approaches for MN treatment.
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