Estrogen-Mediated Regulation of Mitochondrial Gene Expression

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 29; no. 1; pp. 14 - 27
• Main Authors: Lopez Sanchez, Maria I. G, Shearwood, Anne-Marie J, Chia, Tiongsun, Davies, Stefan M. K, Rackham, Oliver, Filipovska, Aleksandra
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.01.2015; Oxford University Press
• Subjects: 3-Hydroxyacyl CoA Dehydrogenases - biosynthesis; 3-Hydroxyacyl CoA Dehydrogenases - genetics; 3-Hydroxyacyl CoA Dehydrogenases - metabolism; Cell Line, Tumor; Estradiol - metabolism; Estrogen Receptor alpha - biosynthesis; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Gene Expression Regulation - genetics; Genes, Mitochondrial - genetics; Humans; MCF-7 Cells; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - metabolism; Original Research; RNA Interference; RNA, Small Interfering
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2014-1077

Estrogens, in particular 17β-estradiol, are well-known regulators of essential cellular functions; however, discrepancies remain over the mechanisms by which they act on mitochondria. Here we propose a novel mechanism for the direct regulation of mitochondrial gene expression by estrogen under metabolic stress. We show that in serum-depleted medium, estrogen stimulates a rapid relocation of estrogen receptor-α to mitochondria, in which it elicits a cellular response, resulting in an increase in mitochondrial RNA abundance. Mitochondrial RNA levels are regulated through the association of estrogen receptor-α with 17β-hydroxysteroid dehydrogenase 10, a multifunctional protein involved in steroid metabolism that is also a core subunit of the mitochondrial ribonuclease P complex responsible for the cleavage of mitochondrial polycistronic transcripts. Processing of mitochondrial transcripts affects mitochondrial gene expression by controlling the levels of mature RNAs available for translation. This work provides the first mechanism linking RNA processing and estrogen activation in mitochondrial gene expression and underscores the coordinated response between the nucleus and mitochondria in response to stress.