Genetically prioritized mitochondrial regulators of advanced renal failure: multi-omic Mendelian randomization and biological plausibility assessment in allograft fibrosis

Background Advanced renal failure remains a major global health burden. Mitochondrial dysfunction is frequently observed during progressive kidney injury and chronic allograft dysfunction (CAD), but observational data cannot distinguish causal involvement from secondary consequences. We applied a multi-omic genetic prioritization framework to evaluate whether inherited variation affecting mitochondrial gene regulation is associated with a proxy phenotype for advanced renal failure and fibrotic allograft remodeling. Methods We integrated cis-mQTL (DNA methylation), cis-eQTL (gene expression), and cis-pQTL (plasma protein) data for MitoCarta3.0 genes with a UK Biobank GWAS of kidney transplant recipient status (369 cases, 397,602 controls) as a proxy endpoint for advanced renal failure. Summary-data-based Mendelian randomization (SMR; Wald ratio) was performed using a single lead cis-QTL instrument per gene per layer, with HEIDI heterogeneity testing and Bayesian colocalization to assess whether molecular QTL and outcome signals were consistent with a shared causal variant (PPH4 ≥ 0.70). Because no association survived false discovery rate (FDR) correction across the mitochondrial gene set, we used a tiered, exploratory prioritization scheme based on nominal MR evidence and colocalization. Instrument strength metrics (F-statistics and R²) are reported. Results At a nominal threshold ( p 0.05; none surviving FDR 0.05), we observed suggestive SMR associations in the methylation and expression layers, with generally weaker signals in the protein layer. Integrating MR evidence with colocalization support prioritized eight mitochondrial candidate genes ( C20orf72 / MGME1 , NDUFA13 , MRPS18C , MTIF3 , ECHDC1 , MTHFD1L , QDPR , and TST ). Translational evaluation showed dysregulation of several prioritized candidates in human CAD allograft tissues and in a murine allogeneic kidney transplantation model of chronic allograft fibrosis. In TGF-β–stimulated HK-2 cells, mitochondrial dysfunction accompanied profibrotic responses, and functional perturbation supported NDUFA13 as a plausible node linking mitochondrial bioenergetics to fibrotic remodeling. Conclusions Given the limited number of outcome cases, the proxy nature of transplant recipient status, and no FDR-significant associations, the genetic results should be interpreted as exploratory and hypothesis-generating rather than causal proof. Nonetheless, multi-omic genetic prioritization with kidney-relevant experimental data highlights mitochondrial pathways as plausible contributors to advanced renal failure and fibrotic allograft remodeling, motivating replication in larger outcome GWAS and kidney-relevant QTL resources.