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Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual
Yannick Das1, Daniëlle Swinkels1, Sai Kocherlakota1
1Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Abstract:
Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
Insights
Loss of multifunctional protein 2 (MFP2) impairs vision by disrupting fatty acid metabolism in the retina. This leads to photoreceptor damage and vision loss, highlighting the importance of peroxisomal beta-oxidation for eye health.
Area of Science:
- Biochemistry
- Ophthalmology
- Cell Biology
Background:
- The peroxisomal β-oxidation pathway, involving multifunctional protein 2 (MFP2), is crucial for metabolizing very long chain fatty acids (VLCFAs) and polyunsaturated fatty acids (PUFAs).
- These fatty acids are abundant in photoreceptor outer segments (POS), and their metabolism is vital for retinal function.
- The precise molecular mechanisms linking MFP2 deficiency to retinopathy have remained unclear.
Purpose of the Study:
- To investigate the role of MFP2 and peroxisomal β-oxidation in retinal integrity and function.
- To elucidate the molecular and metabolic changes in the retina due to MFP2 deficiency.
Main Methods:
- Generation and analysis of mice lacking MFP2.
- Assessment of retinal function and photoreceptor morphology.
- Gene expression profiling of MFP2-deficient retinas.
- Lipidomic analysis of retinal tissues.
Main Results:
- MFP2-deficient mice exhibited reduced retinal function and shortened photoreceptor segments by 3 weeks of age.
- Retinas showed altered gene expression, with decreased phototransduction genes and increased inflammation-related genes.
- Significant reduction in DHA-containing phospholipids and accumulation of very long chain PUFAs (≥34 carbons) were observed.
Conclusions:
- Intact peroxisomal β-oxidation is essential for maintaining retinal integrity.
- MFP2 deficiency disrupts PUFA homeostasis, leading to retinopathy.
- The findings suggest impaired systemic supply and retinal traffic of PUFAs, alongside potential local metabolic defects, contribute to vision loss.
