Molecular insights into codon usage analysis of mitochondrial fission and fusion gene: relevance to neurodegenerative diseases

Abstract

Mitochondrial dysfunction is the leading cause of neurodegenerative disorders like Alzheimer's disease and Parkinson's disease. Mitochondria is a highly dynamic organelle continuously undergoing the process of fission and fusion for even distribution of components and maintaining proper shape, number, and bioenergetic functionality. A set of genes governs the process of fission and fusion. OPA1, Mfn1, and Mfn2 govern fusion, while Drp1, Fis1, MIEF1, and MIEF2 genes control fission. Determination of specific molecular patterns of transcripts of these genes revealed the impact of compositional constraints on selecting optimal codons. AGA and CCA codons were over-represented, and CCC, GTC, TTC, GGG, ACG were under-represented in the fusion gene set. In contrast, CTG was over-represented, and GCG, CCG, and TCG were under-represented in the fission gene set. Hydropathicity analysis revealed non-polar protein products of both fission and fusion gene set transcripts. AGA codon repeats are an integral part of translational regulation machinery and present a distinct pattern of over-representation and under-representation in different transcripts within the gene sets, suggestive of selective translational force precisely controlling the occurrence of the codon. Out of six synonymous codons, five synonymous codons encoding for leucine were used differently in both gene sets. Hence, forces regulating the occurrence of AGA and five synonymous leucine-encoding codons suggest translational selection. A correlation of mutational bias with gene expression and codon bias and GRAVY and AROMA signifies the selection pressure in both gene sets, while the correlation of compositional bias with gene expression, codon bias, protein properties, and minimum free energy signifies the presence of compositional constraints. More than 25% of codons of both gene sets showed a significant difference in codon usage. The overall analysis shed light on molecular features of gene sets involved in fission and fusion.