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Healthy Complex I Function

In healthy mitochondria, Complex I operates as the largest and most complex enzyme of the electron transport chain. It catalyzes the transfer of electrons from NADH to ubiquinone (CoQ10) through a sophisticated mechanism involving multiple iron-sulfur clusters and flavin mononucleotide (FMN). The process follows the "quinol-triggered semi-automatic shotgun model" where electron transfer is coupled to proton pumping across the inner mitochondrial membrane.

The healthy Complex I structure contains 45 subunits, with 7 core subunits (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6) encoded by mitochondrial DNA. These subunits form the proton-pumping machinery that creates the electrochemical gradient essential for ATP synthesis. The electron transfer occurs through a series of iron-sulfur clusters with minimal electron leakage and ROS production.

LHON Mutations and Complex I Dysfunction

LHON mutations primarily affect three critical subunits: ND1 (3460G>A), ND4 (11778G>A), and ND6 (14484T>C). These mutations disrupt the quinol-triggered mechanism in distinct ways:

• ND4 mutations (11778G>A): Severely impair proton pumping by disrupting the coupling between electron transfer and proton translocation, reducing ATP synthesis by 60-80%
• ND1 mutations (3460G>A): Block the quinone binding chamber, preventing proper electron transfer from the iron-sulfur clusters to ubiquinone
• ND6 mutations (14484T>C): Disrupt Complex I assembly and stability, leading to reduced overall enzyme function

The disrupted electron transport leads to electron leakage at the flavin site, generating excessive superoxide radicals. This ROS production overwhelms cellular antioxidant defenses, causing lipid peroxidation, mitochondrial DNA damage, and ultimately retinal ganglion cell apoptosis through the intrinsic apoptotic pathway.