Molecular Basis of Mitochondrial Complex I Disruption by m.14484T>C-Induced Leber Hereditary Optic Neuropathy

Abstract

Lebers Hereditary Optic Neuropathy (LHON) is a rare genetic condition and severe neurological disorder characterized by dysfunctional mitochondria under extreme oxidative stress, resulting in retinal ganglion cell death and subsequent rapid bilateral loss of central vision. The m.14484T>C mutation in the ND6 subunit of mitochondrial complex I is known for inducing LHON, and is a prevalent LHON-associated mutation, yet its mechanism of impairment at the molecular level is currently unresolved. In this study, we explore the biophysical underpinnings of this mutation and its role in LHON through disruption of human complex I function. We consider, using atomistic simulations, the differential thermodynamics and kinetics of coenzyme Q10 binding between the mutant and wild-type forms, altered dynamics of the complex upon mutation, and key interactions between coenzyme Q10 and complex I binding sites. The hydrogen bond network present near and within the coenzyme Q10 binding domain, along with proper hydration of E-channel residues that couple redox chemistry to proton pumping, is found to be critical for complex I stability and quinone binding, which the ND6-centered mutation disrupts. SignificanceSingle missense mutations to mitochondrial complex I can cause Leber Hereditary Optic Neuropathy (LHON), characterized by rapid loss of vision. However, the molecular defects produced by these mutations remain unclear, and largely inaccessible to experimental approaches. Using atomistic molecular dynamics simulations and analysis of quinone binding, we unveil the mechanism of the LHON mutation m.14484T>C in the ND6 subunit of human complex I. The mutation selectively disrupts the oxidized quinone state by increasing its distance from the terminal electron donor N2, and altering dynamic and hydration networks linked to proton pumping. This approach results in a redox-dependent model that explains experimentally observed changes in membrane potential and reactive oxygen species production upon disease-causing complex I mutations.