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The Journal of Neuroscience, December 19, 2007, 27(51):14069-14077; doi:10.1523/JNEUROSCI.4391-07.2007

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Cellular/Molecular
Estradiol In Vivo Regulation of Brain Mitochondrial Proteome

Jon Nilsen, ^* Ronald W. Irwin, ^* Timothy K. Gallaher, and Roberta Diaz Brinton

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, Pharmaceutical Sciences Center, and Program in Neuroscience, University of Southern California, Los Angeles, California 90033

Correspondence should be addressed to Dr. Roberta Diaz Brinton, Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90089. Email: rbrinton{at}usc.edu

We used a combined proteomic and functional biochemical approach to determine the overall impact of 17β-estradiol (E₂) on mitochondrial protein expression and function. To elucidate mitochondrial pathways activated by E₂ in brain, two-dimensional (2D) gel electrophoresis was conducted to screen the mitoproteome. Ovariectomized adult female rats were treated with a single injection of E₂. After 24 h of E₂ exposure, mitochondria were purified from brain and 2D analysis and liquid chromatography-tandem mass spectrometry protein identification were conducted. Results of proteomic analyses indicated that of the 499 protein spots detected by image analysis, a total of 66 protein spots had a twofold or greater change in expression. Of these, 28 proteins were increased in expression after E₂ treatment whereas 38 proteins were decreased in expression relative to control. E₂ regulated key metabolic enzymes including pyruvate dehydrogenase, aconitase, and ATP-synthase. To confirm that E₂-inducible changes in protein expression translated into functional consequences, we determined the impact of E₂ on the enzymatic activity of the mitochondrial electron transport chain. In vivo, E₂ treatment enhanced brain mitochondrial efficiency as evidenced by increased respiratory control ratio, elevated cytochrome-c oxidase activity and expression while simultaneously reducing free radical generation in brain. Results of these analyses provide insights into E₂ mechanisms of regulating brain mitochondria, which have the potential for sustaining neurological health and prevention of neurodegenerative diseases associated with mitochondrial dysfunction such as Alzheimer's disease.

Key words: proteomics; Alzheimer's disease; mitochondria; biomarker; estrogen receptor; therapeutic development

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Received Aug. 13, 2007; accepted Oct. 26, 2007.

Correspondence should be addressed to Dr. Roberta Diaz Brinton, Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90089. Email: rbrinton{at}usc.edu

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