Characterization of mitochondrial DNA mutations in colorectal cancer progression by in silico approach and use as potential biomarkers for diagnosis and prognosis

Abstract

Abstract Background Mitochondrial DNA variants are significant contributors to cancer progression, as evidenced by numerous findings. This study focuses on characterizing mitochondrial DNA mutations in colorectal cancer progression and their potential as biomarkers. Methodology Next generation sequencing technology was employed to analyze mitochondrial DNA variants in tumor and adjacent normal tissues from 25 patients with colon/rectal cancer. In silico prediction tools (SIFT, Polyphen2, Mutation Assessor, and SNP&GO) were utilized to assess the pathogenicity of these variants. Additionally, homology modeling of mutated protein structures was conducted, and molecular dynamic simulations were performed to assess the impact of mutation on protein function. Results Eighteen variants were identified across most tumor tissue samples, located in genes from Complex I, IV, and V. Among the identified variants, the V302M and S461 mutations in the MT-ND5 gene and L137F and L220P mutations in the ATP6 gene were predicted to be deleterious, potentially affecting protein function. 3D structural analysis of both wild-type and mutant proteins of MT-ND5 revealed changes in flexibility for the V302M and S461G mutations. The MT-ATP6 mutations L135F and L220P disrupt the interactions with surrounding residues and affect the overall function of protein. Further changes in protein dynamics of the mutated proteins by molecular dynamic simulations also indicate the effects; the mutations have on protein function. Conclusion MT-ND5 and MT-ATP6 variants could serve as potential biomarkers and drug targets in colorectal cancer. This study underscores the significance of mitochondrial DNA variants in cancer progression.

Keywords

• Colorectal cancer
• OXPHOS
• MT-DNA
• NGS technology
• MT-ND5
• MD simulation