Mitochondrial dysfunction in the pathogenesis of intervertebral disc herniation: a mitochondrial related genome-wide Mendelian randomization analysis

As a degenerative disease, the pathophysiology of intervertebral disc herniation (IDH) closely related to mitochondrial dysfunction. However, the specific molecular mechanisms involved have yet to be precisely established. Here, we employed a two-sample, two-step Mendelian Randomization (MR) approach, along with summary-Data-Based MR, genetic colocalization, full phenomenon association analysis, and GO and KEGG enrichment analysis to investigate the genetical effects of mitochondrial dysfunction on IDH. From the intercross between mitochondrial-related genes and eQTLGen genes, we obtained seven genes (DMPK, EHHADH, SLC25A16, ME3, METTL17, TUFM, NDUFA13) with strong causal association with disc herniation. By SMR and genetic colocalization analysis, we further identify five key genes (EHHADH, METTL17, TUFM, NDUFA13, DMPK) as the direct causal tartgeted genes with no heterogeneity and pleiotropy in the SNPs of the genes. Full phenomenon Mendelian randomization was performed to determine possible side effects of the 5 targeting genes. Finally, we validated the expressions of key genes in the degenerative intervertebral discs tissues by qRT-PCR and double-immunofluorescence examinations, and the results were consistent with the MR analysis. Our study provided genetic support for the relationship between mitochondrial related genes and IDH, implicating potential therapeutic targets for future development. However, more basic experiments need to be finished to validate the role of key genes in the development of IDH.