Figure 2.

A similar mechanism of complex I dysfunction induced by pathogenic LHON mutations and rotenone. A) LHON pathogenic mutations occur in mitochondrial genes encoding for the internal membrane-embedded complex I subunits ND1, ND4 and ND6. These subunits are located in the interface with the peripheral, nuclear-encoded PSST and 49 kDa subunits that form a ramp that allows the electron carrier ubiquinone (CoQ) to reach the iron-sulfur center N2 at its reduction site within complex I. LHON mutations are believed to induce a conformational change that prevents CoQ from reaching its reduction site (asterisks). B) Rotenone has been demonstrated to impair CoQ reduction by blocking its access to the reduction site. High energy electrons (e⁻) not used in CoQ reduction react with oxygen molecules to form superoxide ions, thus increasing oxidative stress.

Abbreviations: CoQ, coenzyme Q; LHON, Leber’s hereditary optic neuropathy.