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Cited by 4Retinal Development and DisordersMetabolism and Genetic DisordersRetinal Diseases and Treatments

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

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Boeck, Myriam, Yagi, Hitomi, Chen, Chuck T., Zeng, Yan, Lee, Deokho, Nian, Shen, Kasai, Taku, Lee, Jeff +11 more·2025·Journal of Advanced Research
DOI 10.1016/j.jare.2025.03.004PMC PMC12684955
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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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  • Dietary DHA supplementation significantly ameliorated disease progression in both Mfp2-/- and Acox1-/- models.

    “Importantly, dietary DHA supplementation significantly ameliorated disease progression in both Mfp2–/– and Acox1–/– models, suggesting that DHA depletion may be a key driver of CNS pathology (Swinkels et al., 2023; Boeck et al., 2025).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Boeck et al., 2025

    The Results section (page unavailable) reports that DHA-fed Acox1 knockout mice had significantly improved retinal cone signaling from P30 to P60, while rod signaling did not change significantly. Boeck et al. thus support a benefit for a retinal measure in the Acox1 model, but not the broader claim that DHA significantly ameliorated disease progression. The paired Mfp2 claim is associated with the other citation, not established by this paper. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Acox1-/- mice show early-onset retinal degeneration marked by photoreceptor loss and shortage of DHA-containing lipids as early as 1 month of age.

    “Recent studies have reported early-onset retinal degeneration, marked by photoreceptor loss and shortage of DHA-containing lipids as early as 1 month of age (Boeck et al., 2025).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Boeck et al., 2025

    The Results (Fig. 4, page not provided) report reduced retinal DHA in Acox1 knockout mice at P30, about one month of age, and the Results on retinal degeneration report impaired rod signaling. But photoreceptor loss at that age is not established: total retinal thickness was unchanged, and the Discussion says thinning of the photoreceptor nuclear layer was observed at five months, not one month. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • DHA depletion may be a key driver of CNS pathology.

    “Importantly, dietary DHA supplementation significantly ameliorated disease progression in both Mfp2–/– and Acox1–/– models, suggesting that DHA depletion may be a key driver of CNS pathology (Swinkels et al., 2023; Boeck et al., 2025).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Boeck et al., 2025

    The Results report that DHA alone significantly improved cone signaling in Acox1 knockout mice, but did not significantly change rod signaling; DHA plus ARA improved rod signaling. The Discussion links depleted DHA to retinal dysfunction, supporting a possible role in neural retinal pathology, but this paper does not establish DHA depletion as a key driver of CNS pathology more broadly or show that DHA alone significantly ameliorated overall disease progression. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Boeck, M., Yagi, H., Chen, C. T., Zeng, Y., Lee, D., Nian, S., Kasai, T., Lee, J., Hirst, V., Wang, C., Neilsen, K., Rodrick, T. C., McCutcheon, A., Yu, M., Lodhi, I. J., Singh, S. A., Aikawa, M., Bazinet, R. P., & Fu, Z.
Affiliations
  • Boston Children's Hospital (US)
  • University of Toronto (CA)
  • Brigham and Women's Hospital (US)
  • NYU Langone Health (US)
  • Washington University in St. Louis (US)
Corresponding author
Fu, Zhongjie
ORCID
Venue
Journal of Advanced Research
Publisher
Elsevier BV
Published
2025-12
Volume
78
Pages
667-680
ISSN
  • 2090-1224 (ISSN-L)
  • 2090-1232
DOI
10.1016/j.jare.2025.03.004
PMC
PMC12684955
OpenAlex
W4408148164
Cited by
4
References
5
Citations by year
2026: 2 · 2025: 2
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Advanced Research (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • Massachusetts Lions Eye Research Fund (77821, R01HL126901, R01HL149302)
  • National Institutes of Health (R01EY017017, R01EY032492, R01HL149302)
  • Kowa Company
  • Boston Children's Hospital (97906, 92214)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords
peroxisomal fatty acid oxidation, peroxisomal disorders, retinal dysfunction, photoreceptors, pyruvate supplementation, docosahexaenoic acid, omega-3 fatty acids, arachidonic acid, omega-6 fatty acids, mitochondrial DNA copy number, mitochondrial metabolism, phototransduction, retinal proteome, dietary supplementation
MeSH terms
Animals, Fatty Acids, Mice, Inbred C57BL, Oxidation-Reduction, Retina, Retinal Diseases, Mice, Knockout, Dietary Supplements, Peroxisomes, Acyl-CoA Oxidase, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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