Introduction: Abnormalities in mitochondrial metabolism have been linked to renal disease however, the precise mechanism underlying its involvement in immunoglobulin A nephropathy (IgAN) remains incompletely elucidated.The objective of this study was to ascertain the impact of biomarkers associated with mitochondrial metabolism on IgAN.Methods: The data related to IgAN were obtained from public databases.The mitochondrial metabolism-related biomarkers in IgAN were identified through various bioinformatics approaches, including machine learning algorithms and expression validation.Subsequently, enrichment analysis and immune microenvironment analysis were conducted to explore biomarkers' potential mechanisms in IgAN.Additionally, single-cell RNA sequencing (scRNA-seq) analysis was performed to identify key cell types and clarify the expression dynamics of biomarkers.The expression levels of the biomarkers were validated via reverse transcription quantitative PCR (RT-qPCR).Results: Two robust biomarkers, CYP27B1 and PCK1, were consistently downregulated in IgAN across training and validation cohorts (P < 0.001), showing excellent diagnostic accuracy (AUC = 0.98-1.00).Both were co-enriched in oxidative phosphorylation and fatty-acid-metabolism pathways, indicating impaired mitochondrial bioenergetics.Immune microenvironment analysis revealed strong positive correlations of CYP27B1 and PCK1 with neutrophils and negative correlations with activated NK cells, linking metabolic dysregulation to immune activation.Single-cell analysis identified proximal tubular cells (PTCs) as the predominant cell population expressing these biomarkers.PCK1 expression increased at early differentiation stages and declined later, while CYP27B1 remained relatively stable.RT-qPCR confirmed significant downregulation of both biomarkers in IgAN samples, consistent with transcriptomic predictions.Conclusion: Integrating bulk and single-cell transcriptomics with experimental validation, this study identifies CYP27B1 and PCK1 as novel mitochondrial metabolism-related biomarkers in IgAN and pinpoints PTCs as key pathological cell types.These findings highlight a mitochondrial-immune axis driving IgAN progression and provide promising targets for non-invasive diagnosis and metabolic intervention.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Hara et al. (Wed,) studied this question.