TY - JOUR
T1 - Estrogen prevents oxidative damage to the mitochondria in Friedreich's ataxia skin fibroblasts
AU - Richardson, Timothy E.
AU - Yu, Amanda E.
AU - Wen, Yi
AU - Yang, Shao Hua
AU - Simpkins, James W.
PY - 2012/4/3
Y1 - 2012/4/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859241592&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0034600
DO - 10.1371/journal.pone.0034600
M3 - Article
C2 - 22509330
AN - SCOPUS:84859241592
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e34600
ER -