A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory Complex I

Variants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establish a priori whether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations. One of the primary CI variants (m.14484T>C/MT-ND6) associated with the Leber hereditary optic neuropathy was used as a test case. This variant was investigated alone or in combination with two additional rare CI variants whose role remains uncertain. We found that the primary variant stiffens CI dynamics in the crucial E-channel region and that one of the other variants, located in the vicinity of the primary one, further worsens the stiffening. This approach may be extended to other variants candidate to exert a pathogenic impact on CI function, or to investigate the interaction of multiple variants. TeaserMolecular dynamics is able to predict the functional impact of variants hitting respiratory complex I mitochondrial genes.