title: Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
abstract: The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. RPE in culture possesses the machinery needed for mitochondrial fatty acid beta-oxidation in vitro. To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes. Human eye and brain sections were stained with antibodies to medium-chain (MCAD) and very long-chain acyl-CoA dehydrogenase (VLCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and mitochondrial trifunctional protein (MTP) harboring LCHAD. Antibodies to 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) and cytochrome c oxidase subunit I (COX I) were used as a reference. VLCAD, MTP, MCAD, SCHAD, MHBD, and COX I antibodies labeled most retinal layers and tissues of the human eye actively involved in oxidative metabolism (extraocular and intraocular muscle, the RPE, the corneal endothelium, and the ciliary epithelium). MTP and COX I antibodies labeled the inner segments of photoreceptors. The choriocapillaris was labeled only with SCHAD and MCAD antibodies. In the brain, the choroid plexus and nuclei of the brain stem were most intensely labeled with beta-oxidation antibodies, whereas COX I antibodies strongly labeled neurons in several regions of the brain. Mitochondrial fatty acid beta-oxidation likely plays a role in ocular energy production in vivo. The RPE rather than the choriocapillaris could be the critical affected cell layer in LCHAD retinopathy. Reduced energy generation in the choroid plexus may contribute to the cerebral edema observed in patients with beta-oxidation defects.
authors.affiliation: Department of Pediatric Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland. Tiina.Tyni@hus.fi
authors.forename: Tiina
authors.initials: T
authors.lastname: Tyni
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
authors.forename: Bruce
authors.initials: B
authors.lastname: Middleton
authors.forename: Tero
authors.initials: T
authors.lastname: Kivelä
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency* / Q000378:metabolism; D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000201:enzymology; D044926:Butyryl-CoA Dehydrogenase / Q000378:metabolism; D002829:Choroid / Q000201:enzymology; D002924:Ciliary Body / Q000201:enzymology; D003315:Cornea / Q000201:enzymology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007498:Iris / Q000201:enzymology; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000378:metabolism; D010084:Oxidation-Reduction; D010857:Pigment Epithelium of Eye / Q000201:enzymology; D012160:Retina / Q000201:enzymology; D012164:Retinal Diseases / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D044926:Butyryl-CoA Dehydrogenase; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D063991:Mitochondrial Trifunctional Protein