Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction

Area of Science:

• Ophthalmology
• Mitochondrial Biology
• Cellular Metabolism

Background:

• Mitochondrial electron transport chain (ETC) dysfunction in the retinal pigment epithelium (RPE) causes photoreceptor degeneration and is linked to age-related macular degeneration.
• Alternative oxidases can mitigate some, but not all, mitochondrial defects.

Purpose of the Study:

• To investigate the effects of expressing an alternative oxidase from *Ciona intestinalis* (AOX) in ETC-deficient murine RPE.
• To assess the consequences of stimulating coenzyme Q oxidation and respiration without ATP generation in the RPE.

Main Methods:

• Adenoviral delivery of AOX specifically to the RPE in a mouse model with ETC deficiency.
• Analysis of RPE cell characteristics, photoreceptor structure and function, and retinal metabolite levels.

Main Results:

• RPE-restricted AOX expression mitigated RPE dedifferentiation, hypertrophy, mTORC1 activation, and metabolic dysfunction (pseudohypoxia, aerobic glycolysis).
• AOX expression improved photoreceptor structure and function, likely due to increased glucose delivery.
• AOX normalized key metabolites (succinate, 2-hydroxyglutarate) and counteracted neural retinal metabolic deficiencies.

Conclusions:

• Targeted AOX expression in RPE is beneficial, improving outer retinal health despite mitochondrial ETC defects.
• Coenzyme Q oxidation in RPE is crucial for photoreceptor survival.
• This study identifies a critical metabolic network for photoreceptor resilience under RPE mitochondrial stress.