Dysfunctional peroxisomal lipid metabolisms and their ocular manifestations

Abstract

Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and organelles but also fuel substrates for energy production. However, our current knowledge of lipid processing in the retina are very limited. Peroxisomes play a critical role in lipid homeostasis and genetic disorders with peroxisomal dysfunction have different types of ocular complications. In this review, we focus on the role of peroxisomes in lipid metabolism, including degradation and detoxification of very-long-chain fatty acids, branched-chain fatty acids, dicarboxylic acids, reactive oxygen/nitrogen species, glyoxylate, and amino acids, as well as biosynthesis of docosahexaenoic acid, plasmalogen and bile acids. We also discuss the potential contributions of peroxisomal pathways to eye health and summarize the reported cases of ocular symptoms in patients with peroxisomal disorders, corresponding to each disrupted peroxisomal pathway. We also review the cross-talk between peroxisomes and other organelles such as lysosomes, endoplasmic reticulum and mitochondria.

Precision Medicines for Retinal Lipid Metabolism-Related Pathologies

“…It is the main cause of retinal dysfunction and eye diseases, contributing to their set-up and progression. The relation between diabetic retinopathy (DR) and lipid abnormality was found in several studies, showing that high circulation of LDL cholesterol is a significant risk factor for diabetic macular edema and retinal hard exudates [2,3].…”

“…Lipids and glucose are fuel substrates for photoreceptor mitochondria. In fact, they are important as a membrane component in cells and organelles, but also fuel substrates for the production of energy [2,3]. Lipids are also a fundamental structural component of cell membranes, because of the phospholipid bilayer structure of biological membranes.…”

Retinopathy of prematurity: Metabolic risk factors

“…Although mitochondria are the primary organelle for fatty acid oxidation, peroxisomes uniquely oxidize very long-chain fatty acids which cannot be processed by mitochondria into shorter chains that can be used. Peroxisomal disorders are associated with retinal ganglion cell loss, and retinal degeneration ( Chen et al, 2022 ; Das et al, 2021 ). In Zellweger syndrome with mutations in PEX genes involved in peroxisomal biogenesis, there is loss of retinal cells (photoreceptors, retinal ganglion cells) and diminished ERG signals.…”

“…In Zellweger syndrome with mutations in PEX genes involved in peroxisomal biogenesis, there is loss of retinal cells (photoreceptors, retinal ganglion cells) and diminished ERG signals. Gene defects in peroxisomal α- and β-oxidation may also cause attenuated light responses, decreased visual acuity, and blindness ( Chen et al, 2022 ; Das et al, 2021 ). Although omega-3 long-chain polyunsaturated fatty acids are primarily obtained from dietary sources, there is some endogenous production from shorter-chain precursors.…”

“…Although omega-3 long-chain polyunsaturated fatty acids are primarily obtained from dietary sources, there is some endogenous production from shorter-chain precursors. Peroxisomes contribute to the endogenous conversion of precursor omega-3 fatty acids to DHA ( Chen et al, 2022 ; Das et al, 2021 ). Oral DHA ethyl ester supplementation improves visual function in patients with peroxisomal disorders ( Noguer and Martinez, 2010 ).…”