Fig. (3).

Schematic drawing outlining the hypothesis that LHON mutations in complex I (mut) may cause a shift in the potential, which is required for permeability transition (PT), towards the normal Δψ, creating an abnormally low voltage threshold for PT [39]. The shift is assumed to be mediated by Ca²⁺ deregulation and enhanced production of reactive oxygen species (ROS) in the mutant mitochondria, which both alter the permeability transition pore. As a consequence of this lowered threshold, a small rotenone-induced Δψ decline may immediately elicit PT leading to a complete and irreversible collapse of Δψ and oxidative phosphorylation. In cells with wild-type complex I (wt), the same rotenone-induced Δψ decline may not be sufficient for opening of the pore. Reconstitution of a normal Δψ may occur by a reversed action of the F₀/F₁-ATP-synthethase on the expense of glycolytic ATP (compensation).