Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H(2)O(2), could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H(2)O(2) on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H(2)O(2) gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H(2)O(2) and oxidative stress induces larger production of H(2)O(2), small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H(2)O(2) diffusion, and the gradients created by tissue variations in H(2)O(2) production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.