Estrogen and the regulation of mitochondrial structure and function in the brain

Arnold, Susanne; Victor, Marion; Beyer, Cordian

doi:10.1016/j.jsbmb.2012.01.012

Cited by 49 publications

(39 citation statements)

References 98 publications

(115 reference statements)

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“…Future experiments will be needed to investigate the specific role of membrane estrogen receptors (including GqMER) in transducing the protective effects of STX on mitochondrial function. Although the mechanisms underlying these effects have not been fully elucidated, manipulations that target PKA signaling have been reported to increase ETC activity in rat hippocampal neurons and to reverse the bioenergetic impairment caused by Aβ treatment [90, 91], while ERK and PI3K activation have been shown to restore ATP production in a neuronal model of mitochondrial injury [92]. As noted above, these same signaling pathways have been implicated in regulating STX-responses in other contexts [67–69].…”

Section: Discussionmentioning

confidence: 99%

STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity

Gray

Zweig

Kawamoto

et al. 2016

JAD

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Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity

Gray

Zweig

Kawamoto

et al. 2016

JAD

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“…In CNS cells from PON2 +/+ male mice, exposure to estradiol (200 nM, 24 h) provided protection toward toxicity induced by the two oxidants. This is not surprising, as neuroprotective actions of estrogens are well known [100–103]. However, the protective effect of estradiol was absent in cells from PON2 −/− mice, suggesting that a major mechanism of estrogen neuroprotection may be represented by induction of PON2 [94].…”

Section: Pon2mentioning

confidence: 99%

Paraoxonases-1, -2 and -3: What are their functions?

Furlong

Marsillach

Jarvik

et al. 2016

Chemico-Biological Interactions

164

122

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Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high-density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual’s functional Q192R genotype and activity levels. The three-dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa’s pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3- to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson’s disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis.

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“…47,56,65,66 Mitochondria ERβ is also found in mitochondria (referred to as mtERβ), where it regulates mitochondrial function and can induce expression of mitochondrial genes ( Figure 3). [67][68][69][70] ERβ is also localized to the mitochondria inter face and communicates with the endoplasmic reticu lum, a region also known as mitochondria associated membranes. 69 mtERβ within mitochondria is uniquely positioned to regulate mitochondriaspecific gene expression, 71 which enables estrogen to regulate energy homeostasis throughout the cell.…”

Section: Plasma Membranementioning

confidence: 99%

“…47,56 Nuclear ERα can also regulate mitochondrial function via modulating the expression of nuclear genes that encode proteins that are targeted to the mitochondria. [69][70][71] Nucleus Estrogenmediated transcription of genes requires trans location of ERα and ERβ into the nucleus. ERα and ERβ dimerize and are transported into the nucleus, which can comprise α or β homodimers or hetero dimers of ERα and ERβ proteins ( Figure 3).…”

Section: Plasma Membranementioning

confidence: 99%

Perimenopause as a neurological transition state

et al. 2015

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Perimenopause is a midlife transition state experienced by women that occurs in the context of a fully functioning neurological system and results in reproductive senescence. Although primarily viewed as a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in the context of their relationship to the network of estrogen receptors that control metabolism in the brain.

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Estrogen and the regulation of mitochondrial structure and function in the brain

Cited by 49 publications

References 98 publications

STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity

STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity

Paraoxonases-1, -2 and -3: What are their functions?

Perimenopause as a neurological transition state

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