6. Abstract The overall aim of this project is to determine the mechanisms and long-term consequences of estrogen on mitochondrial function and metabolism in brain. Our target outcome is sustaining mitochondrial function to sustain neurological health for prevention of neurodegenerative diseases associated with aging and mitochondrial dysfunction. Results of our previous mechanistic analyses indicate that 17?-estradiol (E2) protects against dysregulation of mitochondrial calcium homeostasis, enhances mitochondrial function, increases efficiency of oxidative phosphorylation, protects against oxidative damage and regulates the mitochondrial proteome. In this project, we are testing the global hypothesis that E2 sustains mitochondrial function to promote the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). As a corollary to this hypothesis, we propose that in the female brain, E2-induced enhancement of mitochondria oxphos-coupled glycolysis can prevent decreased glucose utilization characteristic of aging and delay its expression in a female mouse model of Alzheimer's disease (AD). To test these hypotheses, in Specific Aim I we will determine the functional consequences of long-term E2 regulation of key enzymes required for aerobic glycolysis and oxidative phosphorylation in brain, the cellular selectivity of E2 regulation of mitochondria in primary neurons and astrocytes and impact of loss of ovarian hormones and E2 on brain metabolism using microPET imaging.
In Specific Aim II we will investigate the estrogen receptor subtype and signaling mechanisms whereby E2 induces integrated regulation of the mitoproteome and mitochondrial function.
In Specific Aim III we will determine the E2-induced signaling pathway(s) that regulate brain mitochondrial function by investigating (1) the role of estrogen receptor subtypes, the obligatory role of the (2) src/MAPK/CREB and (3) PI3K/Akt pathways and (4) nuclear versus mitochondrial site of action in the E2-induced regulation of the functional mitoproteome.
In Aim III, we will determine the therapeutic efficacy of E2 to sustain mitochondrial function and brain metabolism during aging and reproductive senescence, ovarian hormone deprivation in a mouse model of Alzheimer's disease. Results of these discovery efforts will advance our knowledge of estrogen action in brain mitochondria and its impact on development of neurodegenerative pathology. Further, these analyses will generate insights into early events that lead to mitochondrial dysfunction and the compensatory responses that precede it. Together, these findings could identify biomarkers of mitochondrial function and elucidate strategies to intervene at the earliest stages of dysregulation to prevent mitochondrial dysfunction and subsequent neurodegenerative disease.

Public Health Relevance

Sixty-eight percent of all victims of Alzheimer's disease are postmenopausal women. Our project will investigate estrogen regulation of mitochondrial function as healthy mitochondria are key to sustaining neurological function and preventing neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032236-09
Application #
8306805
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$316,023
Indirect Cost
$120,947
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Rettberg, Jamaica R; Yao, Jia; Brinton, Roberta Diaz (2014) Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 35:8-30
Ding, Fan; Yao, Jia; Zhao, Liqin et al. (2013) Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's. PLoS One 8:e59825
Singh, Meharvan; Simpkins, James W; Simpkins, James W et al. (2013) Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease. Brain Res 1514:1-2
Yao, Jia; Zhao, Liqin; Mao, Zisu et al. (2013) Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor *-selective phytoSERM treatments. Brain Res 1514:128-41
Irwin, R W; Yao, J; To, J et al. (2012) Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J Neuroendocrinol 24:236-48
Hamilton, Ryan T; Rettberg, Jamaica R; Mao, Zisu et al. (2011) Hippocampal responsiveness to 17ýý-estradiol and equol after long-term ovariectomy: implication for a therapeutic window of opportunity. Brain Res 1379:11-22
Yao, Jia; Rettberg, Jamaica R; Klosinski, Lauren P et al. (2011) Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Mol Aspects Med 32:247-57
Yao, Jia; Brinton, Roberta Diaz (2011) Targeting mitochondrial bioenergetics for Alzheimer's prevention and treatment. Curr Pharm Des 17:3474-9
Yao, Jia; Chen, Shuhua; Mao, Zisu et al. (2011) 2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS One 6:e21788
Wu, Tzu-Wei; Chen, Shuhua; Brinton, Roberta D (2011) Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. Brain Res 1379:34-43

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