Department of Biochemistry & Molecular Genetics; Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
J Bioenerg Biomembr. 2017 Aug;49(4):307-324. doi: 10.1007/s10863-017-9704-1.
Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed.
雌激素通过雌激素受体（ER）的差异表达和定位，以细胞特异性的方式，通过直接和间接机制来协调和整合细胞代谢和线粒体活动。雌激素调节转录和细胞信号通路，这些通路汇聚在一起刺激线粒体功能，包括线粒体生物能量学、线粒体融合和裂变、钙稳态以及对抗自由基的抗氧化防御。雌激素通过与经典的基因组雌激素受体α和β（ERα和 ERβ）结合并激活它们，以及通过激活质膜相关的 mERα、mERβ 和 G 蛋白偶联受体（GPER，GPER1）来调节核基因转录。ERα和 ERβ在线粒体和线粒体膜内的定位提供了额外的调节机制。在这里，我们回顾了雌激素和选择性雌激素受体调节剂（SERMs，例如他莫昔芬（TAM））对线粒体生物发生、形态和功能的快速和长期作用的机制，包括核呼吸因子-1（NRF-1，NRF1）转录的调节。NRF-1 是一种核转录因子，它促进线粒体转录因子 TFAM（mtDNA 维持因子 FA）的转录，然后调节 mtDNA 编码基因。雌激素对基因表达的核作用直接控制线粒体生物发生、耗氧量、mtDNA 转录和细胞凋亡。
