Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation.
Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation.
复制标题
DOI：
10.1186/s13041-021-00800-y
复制
发表时间：
2021-06-29
期刊：
影响因子：
3.6
通讯作者：
Lobo MK
中科院分区：
文献类型：
--
作者：
Cole SL;Chandra R;Harris M;Patel I;Wang T;Kim H;Jensen L;Russo SJ;Turecki G;Gancarz-Kausch AM;Dietz DM;Lobo MK
线粒体功能是大脑能量平衡和神经适应所必需的。最近的研究表明，可卡因影响伏核(NAC)内线粒体的动力学和形态特征。此外，可卡因对含有多巴胺受体-1的中棘神经元(D1-MSN)和多巴胺受体-2(D2)-MSN的线粒体有不同的调节作用。然而，人们对可卡因诱导的转录机制及其在调控线粒体过程中的作用知之甚少。在这里，我们证明可卡因增强了转录因子早期生长反应因子3(Egr3)与参与线粒体功能和动力学的核基因的结合。此外，在偶然或非偶然使用可卡因的情况下，以及在啮齿动物模型和人类死后组织中，可卡因暴露调节这些线粒体相关核基因的mRNA。有趣的是，几个线粒体核基因在d1-MSN和D2-MSN中表现出不同的表达谱，可卡因暴露通常会增加d1-MSN中线粒体相关核基因的表达，而不是抑制D2-MSN中的表达。此外，钝化D1-MSN中Egr3的表达可以阻断可卡因对线粒体相关转录辅助激活因子、过氧化物酶体增殖物激活受体γ辅助激活因子(Pgc1α)和线粒体分裂分子动力蛋白相关蛋白1(DRP1)的增强作用。最后，降低D1-MSN Egr3的表达减弱了可卡因诱导的小线粒体的增强，从而证明Egr3调节线粒体的形态适应。总之，这些研究表明，可卡因暴露通过Egr3转录调控线粒体相关核基因转录而影响线粒体的动力学和形态；表明这些分子机制在可卡因暴露发生的神经元功能和可塑性中所起的作用。网上版载有补充材料，可在10.1186/s13041-021-00800-y查阅。
Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure. The online version contains supplementary material available at 10.1186/s13041-021-00800-y.