Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation
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Bibliographic record
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it