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

• DOI: 10.1016/j.ijbiomac.2024.133086
• Publication Date: 2024-06-12T18:37:30Z
• Authors: Laura Rigobello; Francesca Lugli; Leonardo Caporali; Alessio Bartocci; Jacopo Fadanni; Francesco Zerbetto; Luisa Iommarini; Valerio Carelli; Anna Maria Ghelli; Francesco Musiani
• Keywords: Leber's hereditary optic neuropathy; Mitochondria; Molecular dynamics simulations; Pathological variants; 0301 basic medicine; 03 medical and health sciences

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 single or combination of CI variants may impact oxidative phosphorylation. Here we propose computational approach based on coarse-grained molecular dynamics simulations aimed at investigating new variants. One primary associated with Leber hereditary optic neuropathy (m.14484T>C/MT-ND6) was used as test case and investigated alone two additional rare whose role remains uncertain. We that variant positioned E-channel region, which fundamental for function, stiffens enzyme dynamics. Moreover, mechanism transition between π- α-conformation helix carrying proposed. This have implications opening/closing mechanism. Finally, our findings show one variants, located next one, further worsens stiffening, while other does not affect function. be extended candidate exert pathogenic dynamics, investigate interaction multiple