Thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA; also known as ERRα) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptome and ChIP-seq analyses and found that many genes that were co-regulated by both THRB1 and ESRRA were involved in mitochondrial metabolic pathways. These included oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and β-oxidation of fatty acids. TH increased ESRRA expression and activity in a THRB1-dependent manner through the induction of the transcriptional coactivator PPARGC1A (also known as PGC1α). Moreover, TH induced mitochondrial biogenesis, fission, and mitophagy in an ESRRA-dependent manner. TH also induced the expression of the autophagy-regulating kinase ULK1 through ESRRA, which then promoted DRP1-mediated mitochondrial fission. In addition, ULK1 activated the docking receptor protein FUNDC1 and its interaction with the autophagosomal protein MAP1LC3B-II to induce mitophagy. siRNA knockdown of ESRRA, ULK1, DRP1, or FUNDC1 inhibited TH-induced autophagic clearance of mitochondria through mitophagy and decreased OXPHOS. These findings show that many of the mitochondrial actions of TH are mediated through stimulation of ESRRA expression and activity, and co-regulation of mitochondrial turnover through the PPARGC1A-ESRRA-ULK1 pathway is mediated by their regulation of mitochondrial fission and mitophagy. Hormonal or pharmacologic induction of ESRRA expression or activity could improve mitochondrial quality in metabolic disorders.

甲状腺激素受体β1（THRB1）和雌激素相关受体α（ESRRA；也称为ERRα）在线粒体活性中均起重要作用。为了了解它们的潜在相互作用，我们进行了转录组和ChIP-seq分析，发现许多由THRB1和ESRRA共同调控的基因都参与了线粒体的代谢途径。这些包括氧化磷酸化（OXPHOS），三羧酸（TCA）循环和脂肪酸的β-氧化。TH通过诱导转录共激活因子PPARGC1A（也称为PGC1α）以THRB1依赖的方式提高ESRRA的表达和活性。此外，TH以ESRRA依赖性方式诱导线粒体的生物发生，裂变和线粒体吞噬。TH还通过ESRRA诱导自噬调节激酶ULK1的表达，然后促进DRP1介导的线粒体裂变。此外，ULK1激活了对接受体蛋白FUNDC1及其与自噬体蛋白MAP1LC3B-II的相互作用以诱导线粒体吞噬。siRNA敲低ESRRA，ULK1，DRP1或FUNDC1通过线粒体吞噬抑制TH诱导的线粒体自噬清除并降低OXPHOS。这些发现表明，TH的许多线粒体作用是通过刺激ESRRA的表达和活性来介导的，而通过PPARGC1A-ESRRA-ULK1途径对线粒体更新的共同调控是通过其对线粒体裂变和线粒体的调控来介导的。ESRRA表达或活性的激素或药理学诱导作用可改善代谢性疾病中线粒体的质量。