Estradiol<i>In Vivo</i>Regulation of Brain Mitochondrial Proteome

Nilsen, Jon; Irwin, Ronald W.; Gallaher, Timothy K.; Brinton, Roberta Dı́az

doi:10.1523/jneurosci.4391-07.2007

Cited by 161 publications

(192 citation statements)

References 46 publications

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“…1705226) revealed that there are at least two 86% homologous CREB sequences present in the genome (Sarkar et al, 2008, unpublished observation). Consistently, estrogens have been found to increase expression of mitochondrial coded cytochrome c oxidase subunits I, II, and II (Chen et al, 2004b;Chen et al, 2005;Hsieh et al, 2006;Nilsen et al, 2007;Yager and Chen, 2007).…”

Section: Erβ As a Mitochondrial Transcriptional Factormentioning

confidence: 86%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

135

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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Section: Erβ As a Mitochondrial Transcriptional Factormentioning

confidence: 86%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

135

105

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“…Raben et al found that β-hydroxyacyl-CoA dehydrogenase (HADH) and CS levels were 20% lower in formerly obese women [46] . Moreover, pyruvate dehydrogenase, aconitase, and ATP-synthase are regulated by estrogen [47] . Therefore, more precursor acetyl-CoA may enter into the fatty acid, ketone (eg, acetoacetate, 3-hydroxy-butanoic acid, and acetone), and cholesterol biosynthesis processes as a result of the TCA cycle being attenuated under estrogen deficiency.…”

Section: Discussionmentioning

confidence: 99%

GC-TOF/MS-based metabolomic profiling of estrogen deficiency-induced obesity in ovariectomized rats

Zhang

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To explore the alteration of endogenous metabolites and identify potential biomarkers using metabolomic profiling with gas chromatography coupled a time-of-flight mass analyzer (GC/TOF-MS) in a rat model of estrogen-deficiency-induced obesity. Methods: Twelve female Sprague-Dawley rats six month of age were either sham-operated or ovariectomized (OVX). Rat blood was collected, and serum was analyzed for biomarkers using standard colorimetric methods with commercial assay kits and a metabolomic approach with GC/TOF-MS. The data were analyzed using multivariate statistical techniques. Results: A high body weight and body mass index inversely correlated with serum estradiol (E2) in the OVX rats compared to the sham rats. Estrogen deficiency also significantly increased serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Utilizing GC/TOF-MS-based metabolomic analysis and the partial least-squares discriminant analysis, the OVX samples were discriminated from the shams. Elevated levels of cholesterol, glycerol, glucose, arachidonic acid, glutamic acid, glycine, and cystine and reduced alanine levels were observed. Serum glucose metabolism, energy metabolism, lipid metabolism, and amino acid metabolism were involved in estrogen-deficiency-induced obesity in OVX rats. Conclusion: The series of potential biomarkers identified in the present study provided fingerprints of rat metabolomic changes during obesity and an overview of multiple metabolic pathways during the progression of obesity involving glucose metabolism, lipid metabolism, and amino acid metabolism.

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“…Protein concentrations were determined using the BCA protein assay kit (Pierce). Western blot analysis was similar to a published procedure with minor modifications (36,37). Detailed methods are provided in the SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Yao

Irwin

Zhao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

841

743

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Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (A␤) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of A␤ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.ABAD ͉ aging ͉ bioenergetics ͉ brain hypometabolism ͉ mitochondria T he essential role of mitochondria in cellular bioenergetics and survival has been well established (1-3). Previous studies have suggested that mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) (1, 4). Alzheimer's pathology is accompanied by a decrease in expression and activity of enzymes involved in mitochondrial bioenergetics, which would be expected to lead to compromised electron transport chain complex activity and reduced ATP synthesis (5). Further, in AD there is a generalized shift from glycolytic energy production toward use of an alternative fuel, ketone bodies. This is evidenced by a 45% reduction in cerebral glucose utilization in AD patients (6), which is paralleled by decrease in the expression of glycolytic enzymes coupled to a decrease in the activity of the pyruvate dehydrogenase (PDH) complex (5). Patients with incipient AD exhibit a utilization ratio of 2:1 glucose to alternative fuel, whereas comparably aged controls exhibit a ratio of 29:1, whereas young controls exclusively use glucose as with a ratio of 100:0 ratio (7). In addition to t...

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EstradiolIn VivoRegulation of Brain Mitochondrial Proteome

Cited by 161 publications

References 46 publications

Estrogen actions on mitochondria—Physiological and pathological implications

Estrogen actions on mitochondria—Physiological and pathological implications

GC-TOF/MS-based metabolomic profiling of estrogen deficiency-induced obesity in ovariectomized rats

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

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