Computational Investigation on Cytochrome C Oxidase Subunit 3(Mt-co3) Responsible for Leber Hereditary Optic Neuropathy(Lhon)

Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by subacute, painless central vision loss resulting from the degeneration of retinal ganglion cells. While LHON research has traditionally focused on mutations in mitochondrial Complex I subunits, the role of Complex IV remains less explored. This study employs a comprehensive in silico pipeline to investigate the pathogenic potential of non-synonymous single nucleotide polymorphisms (nsSNPs) in the Cytochrome c Oxidase Subunit 3 ( MT-CO3 ) gene. An initial screening of 261 nsSNPs using SIFT, PolyPhen-2, PANTHER, and PhD-SNP identified six highly deleterious and conserved variants: H3R, G78S, V91I, V91L, A200T, and F251L. Among these, the F251L mutation was consistently predicted to be the most damaging across all bioinformatic platforms. While stability analyses via I-Mutant 2.0 and DynaMut2 suggested a localized gain in thermodynamic stability for F251L, 100 ns Molecular Dynamics (MD) simulations revealed significant global structural deviations. The F251L mutant exhibited higher RMSD and RMSF values compared to the wild-type, indicating that the mutation disrupts the dynamic equilibrium and structural flexibility of the protein. These findings suggest that the F251L variant in MT-CO3 significantly impairs mitochondrial respiration, contributing to the energy deficit that triggers optic nerve degeneration in LHON.