Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual...

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.