title: Estrogen prevents oxidative damage to the mitochondria in Friedreich's ataxia skin fibroblasts.
abstract: Estrogen and estrogen-related compounds have been shown to have very potent cytoprotective properties in a wide range of disease models, including an in vitro model of Friedreich's ataxia (FRDA). This study describes a potential estrogen receptor (ER)-independent mechanism by which estrogens act to protect human FRDA skin fibroblasts from a BSO-induced oxidative insult resulting from inhibition of de novo glutathione (GSH) synthesis. We demonstrate that phenolic estrogens, independent of any known ER, are able to prevent lipid peroxidation and mitochondrial membrane potential (ΔΨm) collapse, maintain ATP at near control levels, increase oxidative phosphorylation and maintain activity of aconitase. Estrogens did not, however, prevent BSO from depleting GSH or induce an increased expression level of GSH. The cytoprotective effects of estrogen appear to be due to a direct overall reduction in oxidative damage to the mitochondria, enabling the FRDA fibroblast mitochondria to generate sufficient ATP for energy requirements and better survive oxidative stress. These data support the hypothesis that phenol ring containing estrogens are possible candidate drugs for the delay and/or prevention of FRDA symptoms.
authors.affiliation: Institute for Aging and Alzheimer's Disease Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Richardson
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005621:Friedreich Ataxia / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000473:pathology*
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D000255:Adenosine Triphosphate; D000154:Aconitate Hydratase; D005978:Glutathione