# Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection

## TL;DR

This study explores a metabolic approach to reverse mitochondrial dysfunction in glaucoma caused by a specific optineurin mutation.

## Contribution

The study identifies ACLC-mediated mitochondrial leak as a key driver of metabolic dysfunction in E50K-OPTN glaucoma and proposes a potential therapeutic strategy.

## Key findings

- E50K-OPTN fibroblasts show reversed ATP synthase activity and increased mitochondrial proton leak.
- Dexpramipexole treatment normalizes ATP synthase function and reduces protein synthesis rates.
- Dexpramipexole lowers p62 levels, indicating reduced mitophagic burden in E50K fibroblasts.

## Abstract

Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.