The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy

Abstract

Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber's hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.

Keywords: Leber’s hereditary optic neuropathy; drugs; environmental factors; mitochondrial disease; neurodegeneration; optic neuropathy.

Figure 1

Graphic representation of visual impairment in LHON. Front view photograph of three people was generated with artificial intelligence using the AI image generator from MyEdit (myedit.online) (left), submitted to patients, and then processed by the authors according to the indications of the patients to best represent how they perceive the original photograph. Shown are illustrations of visual perception after the recent onset of LHON (middle) or in chronic LHON (right). Note the spared peripheric zones (middle,right).

Figure 2

Graphic representation of retina cell organization (left) and of the optic pathways (right). The yellow and purple pathways correspond to the left and right visual fields, respectively. RNFL: retinal neural fiber layer.

Figure 3

Graphic summary of the ETC and OXPHOS. The five protein complexes (CI–V) are embedded in the inner mitochondrial membrane. Complex I and complex II catalyze the reduction of ubiquinone (CoQ10) to ubiquinol (CoQ10H₂) upon oxidation of nicotinamide adenine dinucleotide (NADH/NAD+) or flavin adenine dinucleotide (FADH₂/FAV), respectively. Complex III catalyzes the reduction of cytochrome c (o.cytC) upon oxidation of CoQ10H₂. Complex IV catalyzes the reduction of dioxygen to water upon oxidation of reduced cytochrome c (r.cytC). Protons are released into the intermembrane space at each step and are driven back into the mitochondrial matrix through complex V, which generates ATP from ADP.

Figure 4

Molecular structures of the benzoquinones CoQ10, CoQ10H₂, idebenone, idebenol, QS10 and EPI-743.

Figure 5

Schematic representation of the main mechanisms of idebenone, EPI-743, and elamipretide. EPI-743 can reduce oxidative stress and ferroptosis, particularly by supporting the conversion of oxidized glutathione (GSSG) to its reduced form (GSH). IDB can be converted to QS10 by metabolism (oxidative shortening). Idebenone (IDB) and QS10 can be reduced by NQOs (NQO) to idebenol (IDBH2) and QS10H2, respectively. IDBH2, QS10H2, and EPI-743 can bypass mutated complex I (mt CI) and thus relaunch electron transfer to and from complex III (CIII). Elamipretide (MTP-131) inhibits the conversion of cardiolin (CL) and cytochrome c to their peroxidated forms (per.CL and per.cytC, respectively). This preserves CL function and prevents the release of cytochrome c into the cytoplasm, where it could induce apoptosis upon binding to apoptotic protease activating factor 1 (Apaf-1) and caspase-9 (Casp9). Electron flow is depicted as blue arrows (solid: normal, dotted: defective). CIV: complex IV, CV: complex V.

Figure 6

Graphic summary of the main environmental factors known or assumed to be protective or harmful for LHON carriers.