A theory on the pathogenesis of Leber hereditary optic neuropathy: Two hits and the role of light toxicity

Document Type

Article

Publication Date

5-2025

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that leads to rapid, often irreversible central visual loss. While the mitochondrial inheritance of LHON was clarified in 1988, key aspects of its pathophysiology remain unexplained, particularly its selective impact on retinal ganglion cells (RGCs). Conventional hypotheses attribute this specificity to RGCs’ small, unmyelinated axons; however, these characteristics exist in other unaffected central nervous system (CNS) areas. Here, we propose that light exposure acts as a critical cofactor in mitochondrial dysfunction, contributing to RGC susceptibility in LHON. Unlike other CNS tissues, RGC axons in the retinal nerve fiber layer are highly exposed to light, which may disrupt mitochondrial function by generating reactive oxygen species (ROS) and increasing mitochondrial DNA (mtDNA) mutation rates. Given that retinal mitochondria contain numerous chromophores that may act as photosensitizers, the retina's high metabolic activity combined with this unprotected light exposure could uniquely predispose RGCs to mitochondrial damage in LHON. This hypothesis provides a novel framework for understanding LHON's cell specificity and opens possibilities for broader applications, including other optic neuropathies where light exposure and mitochondrial vulnerability intersect. Future research should examine the impact of light protection on LHON progression and test for higher LHON prevalence in northern latitudes or seasonal shifts. Our approach underscores the need for further investigation into the role of environmental factors in LHON, opening a door to novel ways for prevention and intervention for patients with this neuropathy.

Publication Title

Medical Hypotheses

Volume

198

Comments

This article was published in Medical Hypotheses, Volume 198.

The published version is available at https://doi.org/10.1016/j.mehy.2025.111623.

Copyright © 2025 Elsevier Ltd.

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