Mendelian Randomization Analysis of Mitochondria-Related Genes and Screening of Prognostic Genes in Colorectal Cancer.

Background: Mitochondria have been linked with inflammatory colorectal cancer (CRC) development; however, the association between mitochondria-related genes (MRGs) and CRC remains unknown.

Aims: To explore the causal relationship between MRGs and CRC, screen prognostic genes, conduct drug prediction analyses, and investigate the correlations between prognostic genes and immune cells.

Materials And Methods: We obtained 1136 MRGs from the MitoCarta3.0 database and analyzed the causal relationship between MRGs expression, methylation, and protein abundance and CRC by Mendelian randomization and sensitivity testing. Prognostic genes were screened via protein-protein interaction networks, enrichment, multi-omics, and survival analyses. Selected key genes were subjected to drug prediction analyses. The prognostic genes and immune cell correlations were explored using Spearman's correlation.

Results: The results indicated that 44 MRGs showed causal relationships with CRC. Six genes (sterol carrier protein2 [SCP2], ATP binding cassette subfamily D member 3 [ABCD3], cytochrome coxidase assembly factor heme A: farnesyltransferase [COX10], mitochondrial contact site and cristae organizing system subunit 10 [MiCOS 10], glutaryl-Coenzyme A dehydrogenase [GCDH], and mitochondrial translational release factor 1-like [MTRF1L] were causally associated with CRC and showed better prognostic significance when their expression levels were high, and there were 106 drugs targeting them. SCP2, ABCD3, MICOS10, GCDH, and MTRF1L were associated with most immune cells, while COX10 was not associated with any of the 96 immune cells.

Discussion: The identification of causal MRGs and their prognostic significance provides new insights into mitochondria's role in CRC. Drug prediction and immune correlations may guide therapy, but validation in larger cohorts and models is needed.

Conclusion: This study reveals causal associations between specific MRGs and CRC, identifies prognostic genes with therapeutic potential, and clarifies immune cell relationships, advancing CRC pathogenesis understanding and treatment development.