Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation

Abstract

Introduction: Dyslipidemia contributes to many retinal diseases, but underlying lipid processing pathways are not fully understood. Peroxisomes oxidize very long-chain fatty acids and generate docosahexaenoic acid (DHA). Mutations in peroxisomal genes can result in severe neural retinal dysfunction. However, therapeutic approaches for peroxisomal diseases remain scarce, and dietary strategies yield inconsistent results.

Objectives: This study sought to elucidate retinal metabolic adaptations resulting from impaired peroxisomal fatty acid oxidation and to evaluate the therapeutic potential of nutrient supplementation in peroxisomal retinal disease.

Methods: In mice with global knockout (KO) of acyl-coenzyme A oxidase 1 (Acox1), encoding the first and rate-limiting enzyme in peroxisomal fatty acid oxidation, the retina was characterized at postnatal day (P) 30 during development. Retinal thickness, photoreceptor structure, and function were examined. Proteome analysis was utilized for molecular mechanistic investigation. Metabolomics and fatty acid profiling were conducted to study metabolic alterations in the retina. Nutrient intervention was performed to test if providing deficient nutrients could attenuate the observed retinal dysfunction.

Results: In P30 Acox1 KO mice, we observed impaired neural retinal signaling, accompanied by reduced expression of genes involved in phototransduction. Proteomics suggested diminished glucose and mitochondrial metabolism, supported by decreased mitochondrial number and mitochondrial DNA copy number. Metabolomics showed reduced abundance of retinal pyruvate, and pyruvate supplementation from P30-P60 attenuated neural retinal dysfunction in Acox1 KO mice at P60. Furthermore, Acox1 KO mice at P30 exhibited a significant decrease in omega-3 (n-3) fatty acids and a compensatory increase in n-6 fatty acids. Dietary supplementation with DHA (n-3) or DHA plus arachidonic acid (n-6) from P30-P60 mitigated the progression of retinal dysfunction in Acox1 KO mice.

Conclusion: Retinal dysfunction, decreased mitochondrial number, and metabolic imbalance were observed in mice with impaired peroxisomal fatty acid oxidation. Nutrient intervention may offer a promising therapeutic approach for peroxisomal diseases.

Keywords: ACOX1; DHA; Dyslipidemia; Peroxisomes; Retinal degeneration; Retinal metabolism.