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Transcriptomic and genetic evidence highlights EHHADH in a FUNDC1-associated mitochondrial network in diabetic
Yuzhi Chen1, Demei Ying2, Xuli Guo1
1Hebei Key Laboratory of Medical Data Science, School of Medicine, Hebei University of Engineering, Handan, Hebei Province, 056038, China.
Background:
Diabetic nephropathy (DN) is a major microvascular complication of diabetes and the leading cause of end-stage renal disease. Glomerular and tubular injury, mitochondrial dysfunction, and impaired mitophagy are core factors driving the progression of DN. Recent studies have identified FUNDC1 as a crucial mitophagy receptor; however, its regulatory mechanism in DN remains poorly elucidated.
Methods:
This study integrated compartmental transcriptomics, gene interaction network analysis, and summary-data-based Mendelian randomization (SMR) for systematic research. Differentially expressed genes (DEGs) were extracted from the glomerular dataset GSE96804 and the tubular dataset GSE294519. The intersecting genes of these DEGs with FUNDC1-interacting genes and mitochondrial dysfunction-related genes were obtained to screen core hub genes. Combined with renal expression quantitative trait locus (eQTL) data and DN genome-wide association study (GWAS) data, SMR analysis was performed. Functional enrichment analysis, gene set enrichment analysis (GSEA), and upstream transcription factor prediction were further conducted.
Results:
A total of 5560 DEGs were screened based on adjusted P values (Padj), including 2625 glomerular DEGs, 3199 tubular DEGs, and 264 common DEGs. Twenty FUNDC1-related core hub genes were finally identified, which were mainly enriched in mitophagy and mitochondrial energy metabolism pathways. After correction and screening via the HEIDI test, Transcriptomic and genetic evidence highlights EHHADH in a FUNDC1-associated mitochondrial network in diabetic nephropathy, and its expression was downregulated in DN lesional tissues. FUNDC1 and EHHADH were both associated with mitochondrial metabolic pathways, and E2F4 was predicted to be their common upstream regulatory factor.
Conclusions:
Multi-dimensional results suggest that EHHADH may represent a candidate gene within a FUNDC1-associated mitochondrial regulatory network in DN. The coordinated expression patterns of FUNDC1 and EHHADH suggest their potential involvement in mitochondrial homeostasis-related processes during DN progression.
