Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease.
Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease.
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DOI：
10.1016/b978-0-12-394816-8.00010-6
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
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作者：
Yao, Jia;Brinton, Roberta Diaz
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，具有复杂的进行性病理表型，其特征首先是代谢减退和线粒体生物能量学受损，其次是病理负荷。越来越多的证据表明，在AD发病机制中，线粒体生物能缺陷和脑代谢低下与线粒体氧化应激增加相结合是一种先行和潜在的因果作用。有氧糖酵解途径受损与氧化应激相结合，首先伴随着向生酮途径的转变，最终进展为脂肪酸氧化（FAO）途径，并导致白色物质变性和β-淀粉样蛋白的过度产生和线粒体蓄积。雌激素诱导的信号传导途径会聚在线粒体上以增强线粒体功能并维持有氧糖酵解，再加上柠檬酸循环驱动的氧化磷酸化以增强ATP（三磷酸腺苷）的产生。除了增强线粒体生物能量学，雌激素还通过维持钙稳态、促进抗氧化剂防御自由基、有效的胆固醇运输和β淀粉样蛋白清除来增强神经存活和健康。值得注意的是，当在患病神经元中激活时，E2作用机制收敛到线粒体上也是潜在的脆弱点，其通过增加钙稳态失调的负荷而加剧退化。“雌激素作用的健康细胞偏好”假说研究了调节线粒体功能和生物能量学在促进神经健康中的作用，以及雌激素暴露后导致不同结果的机械十字路口。随着神经健康的连续体从健康发展到不健康，雌激素或激素治疗的好处也是如此。
Alzheimer’s disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The “healthy cell bias of estrogen action” hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.