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

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.

New Discoveries in Retinal Cell Degeneration and Retinal Diseases

“…of visual electrophysiology to monitor the retinal and optic nerve toxicity of medications. Lambiri and Levin's findings [13] correlate well with clinical observations of central loss of the 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. Haider et al [14].…”

In Vivo Imaging of Secondary Neurodegeneration Associated With Phosphatidylserine Externalization Along Axotomized Axons

“… 12 – 19 We have modeled the effects of secondary degeneration in understanding the spread of injury in Leber hereditary optic neuropathy. 20 , 21 However, the mechanisms for axonal secondary degeneration in this model is unclear and could be due to reactive oxygen species or other diffusible mediators. 20 , 21 It is also possible that the spread of axonal injury is related to PS externalization, which is an “eat-me” signal for macrophages or other phagocytic cells.…”

“… 20 , 21 However, the mechanisms for axonal secondary degeneration in this model is unclear and could be due to reactive oxygen species or other diffusible mediators. 20 , 21 It is also possible that the spread of axonal injury is related to PS externalization, which is an “eat-me” signal for macrophages or other phagocytic cells. 22 , 23 An activation of phagocytosis of primarily injured axons could result in a bystander effect for adjacent axons within the same axonal bundle.…”

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

“…ATP depletion would impair axon function long before leading to a wave of apoptosis as is seen clinically in LHON ( 4 ). Furthermore, ATP depletion is relatively minor compared with increased ROS production as noted in cybrid and animal models of LHON ( 5 , 7 , 8 ).…”

“…The G>A mutation leads to the substitution of alanine with threonine at position 52. This results in a relatively modest loss of energy production (ATP), but a more severe increase in ROS production which appears to be the basis of injury to retinal ganglion cells (RGCs) that leads to blindness ( 7 ). ROS production occurring at complex I is largely due to impaired transfer of electrons to CoQ10.…”