Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice
Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice
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DOI：
10.1210/en.2014-1913
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发表时间：
2015-08-01
期刊：
影响因子：
4.8
通讯作者：
Guennoun, Rachida
中科院分区：
文献类型：
--
作者：
Gaignard, Pauline;Savouroux, Stephane;Guennoun, Rachida
性类固醇调节正常和病理状态下的脑功能。线粒体是类固醇的一个重要靶点，这是由17 - β -雌二醇或孕酮（PROG）对卵巢切除的雌性啮齿动物的实验所证明的，但内源性性类固醇的影响仍未得到充分研究。为了解决这个问题，我们分析了线粒体氧化应激、氧化磷酸化系统和脑类固醇水平在3种不同的内分泌条件下的实验。第一组被设计用来研究激素介导的年轻雄性和雌性小鼠的性别差异，完整的和性腺切除后。第二组研究了年轻雌性小鼠在发情周期的3个时间点，以分析类固醇水平的短暂变化的影响。第三组涉及评估永久性减少雄性和雌性老年小鼠的性腺类固醇的影响。我们的研究结果表明，与年轻成年雄性相比，年轻成年雌性具有较低的氧化应激和较高的还原烟酰胺腺嘌呤二核苷酸（NADH）相关呼吸速率，这与较高的丙酮酸脱氢酶复合物活性有关。这种性别差异不依赖于发情周期的阶段，被卵巢切除术抑制，但没有被睾丸切除术抑制，并且在老年小鼠中不再存在。伴随的脑类固醇分析显示，在生殖期间，雌性孕烯醇酮和PROG脑水平高于雄性，并随着年龄的增长而下降。这些发现表明，脑孕烯醇酮和PROG水平的主要男性/女性差异可能导致脑线粒体功能的性别差异。
Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17 beta-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.