Leber's Hereditary Optic Neuropathy (LHON) mtDNA mutations cause cell death by overproduction of reactive oxygen species

LHON cases are due to point mutations of mtDNA affecting Complex I. Complex I is the first in a series of redox reactions along the mitochondrial inner membrane in which electrons are transferred. In LHON, ATP may be reduced and reactive oxygen species (ROS) overproduced. The actual pathophysiology of Complex I is just starting to be understood. In the Wallace mouse model, the mtDNA ND6 mutation in Complex I produces defects in oxidative phosphorylation and RGC loss. However the mouse synaptosomes demonstrated increased ROS without diminution of ATP production. Hence, ROS production at Complex I is important. We propose that alterations of the Complex I proteins disrupt the distance of electron transfer at the iron-sulfate clusters. Mathematical analysis shows that if electrons only cross < 14 angstroms, then quantum electron tunneling (QET) is possible. The criticality of this distance may depend upon proteins that surround the cluster. Mutations that increase this critical distance may convert a QET electron transfer to a traditional chemical one. Thermodynamically, this will not only decrease the efficiency of electron transfer but also produce free electrons which lead to ROS overproduction and RGC death.