Biomolecules. 2022 Oct 2;12(10):1411. doi: 10.3390/biom12101411.
ABSTRACT
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 H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 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.
PMID:36291620 | PMC:PMC9599876 | DOI:10.3390/biom12101411