Targets for Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by acute or subacute loss of central vision due to degeneration of retinal ganglion cells (RGCs) and their axons. The pathogenesis is primarily linked to mitochondrial dysfunction, increased oxidative stress, and apoptotic cell death in the optic nerve. Understanding the molecular targets involved in these processes is critical for elucidating the disease mechanisms, identifying therapeutic opportunities, and guiding drug development. Among the targets listed, only those with direct mechanistic relevance to LHON pathogenesis—specifically those involved in oxidative stress (e.g., glutathione-disulfide reductase, NADPH oxidase 3), mitochondrial redox homeostasis, and neuronal survival—are included. These targets help explain the molecular basis of RGC vulnerability in LHON, offer biomarkers for disease progression, and serve as rational points for therapeutic intervention, such as antioxidant therapies or gene modulation. By focusing on these targets, research and drug development can be more precisely directed toward mitigating the key drivers of neuronal injury in LHON.

Oxidative Stress And Redox Homeostasis

This category includes targets directly involved in the regulation of oxidative stress and redox balance, which are central to the pathogenesis of LHON. Mitochondrial dysfunction in LHON leads to increased reactive oxygen species (ROS) production and impaired antioxidant defense, resulting in RGC damage. The included targets are Glutathione-Disulfide Reductase (GSR) and NADPH Oxidase 3 (NOX3), both of which play critical roles in modulating cellular redox status. Their dysregulation contributes to oxidative damage and neuronal apoptosis in LHON.

Glutathione-Disulfide Reductase (GSR)

Glutathione-Disulfide Reductase (GSR) is a key mitochondrial enzyme that maintains cellular redox homeostasis by catalyzing the reduction of glutathione disulfide (GSSG) to the sulfhydryl form, glutathione (GSH), which is a major intracellular antioxidant. Structurally, GSR is a homodimeric flavoprotein containing FAD- and NADPH-binding domains. Its activity is regulated by NADPH availability and oxidative stress levels. (Entrez: 2936, KEGG: 2936, UniProt: P00390). In LHON, impaired mitochondrial function leads to increased ROS and glutathione depletion, making RGCs particularly susceptible to oxidative injury. Reduced GSR activity exacerbates this vulnerability, as evidenced by decreased GSH/GSSG ratios in LHON models and patient-derived cells (Yu-Wai-Man et al., Brain, 2011). GSR's role is indirect but critical for maintaining the antioxidant capacity necessary to counteract the increased ROS in LHON. Therapeutically, GSR is a biomarker for oxidative stress, and upregulation of its activity or GSH supplementation has shown promise in preclinical LHON models. No direct GSR-targeting drugs are approved for LHON, but antioxidant strategies (e.g., idebenone) aim to restore redox balance, indirectly supporting GSR function.

NADPH Oxidase 3 (NOX3)

NADPH Oxidase 3 (NOX3) is a member of the NOX family of enzymes that catalyze the reduction of oxygen to superoxide using NADPH as an electron donor. NOX3 is a multi-subunit membrane-bound complex with regulatory domains controlling activation by cytosolic subunits. (Entrez: 50508, KEGG: 50508, UniProt: Q9HBY0). While NOX3 is predominantly expressed in the inner ear, NOX family enzymes are implicated in neuronal oxidative stress. In LHON, upregulation of NOX activity (notably NOX2/NOX4, but NOX3 may also contribute) exacerbates mitochondrial ROS production, promoting RGC apoptosis (Carelli et al., Hum Mol Genet, 2004). NOX-derived ROS act synergistically with defective mitochondrial respiration to overwhelm antioxidant defenses. Inhibition of NOX activity has been shown to reduce oxidative damage and preserve RGCs in LHON models. Although NOX3-specific inhibitors are not clinically validated for LHON, pan-NOX inhibitors or antioxidants targeting this pathway are under investigation, highlighting its therapeutic relevance.