iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector.

Purpose: Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE.

The LCHADD Mouse Model Recapitulates Early-Stage Chorioretinopathy in LCHADD Patients.

Purpose: Recent studies have shown that the retinal pigment epithelium (RPE) relies on fatty acid oxidation (FAO) for energy, however, its role in overall retinal health is unknown. The only FAO disorder that presents with chorioretinopathy is long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Studying the molecular mechanisms can lead to new treatments for patients and elucidate the role of FAO in the RPE.

A review of fatty acid oxidation disorder mouse models.

Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients.

A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy.

The kynurenine pathway is essential for rhodoquinone biosynthesis in .

A key metabolic adaptation of some species that face hypoxia as part of their life cycle involves an alternative electron transport chain in which rhodoquinone (RQ) is required for fumarate reduction and ATP production. RQ biosynthesis in bacteria and protists requires ubiquinone (Q) as a precursor. In contrast, Q is not a precursor for RQ biosynthesis in animals such as parasitic helminths, and most details of this pathway have remained elusive.