Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function

Abstract

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 ,, , or 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.

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

“…Using ChIP-seq, they showed that MTOR and ESRRA share many target genes, and interact with each other in similar regulatory regions of these genes on a genome-wide scale [61]. Likewise, TH regulates ESRRA transcriptional activity by enhancing PPARGC1A expression and stimulating ESRRA expression [62]. Interestingly, ChIP-seq analysis also shows that there are a significant number of genes that contain both TH receptor beta (THRB) and ESRRA binding sites in the promoters of common target genes involved in mitochondrial oxidative phosphorylation (OXPHOS), the TCA cycle, etc.…”

“…Interestingly, ChIP-seq analysis also shows that there are a significant number of genes that contain both TH receptor beta (THRB) and ESRRA binding sites in the promoters of common target genes involved in mitochondrial oxidative phosphorylation (OXPHOS), the TCA cycle, etc. [62], raising the possibility that they co-regulate these genes.…”

“…Transcriptome data from different tissues show that ESRRA-PPARGC1A regulates hundreds of genes involved in OXPHOS, the TCA cycle, fatty acid beta-oxidation (FAO), and glucose and lipid metabolism [1,14,[20][21][22]27,65]. Moreover, ESRRA also regulates mitochondrial biogenesis, mitophagy, and mitochondrial turnover by directly inducing TFB2M, TFAM, NRF1, MFN2, and SIRT3 gene expression [62,67]. The TFB2M, MFN2, and SIRT3 promoters contain functional ESRR binding sites that activate transcription by recruiting the ESRRA-PPARGC1A complex [67,68].…”

“…In the liver, TH induces the expression of ESRRA, which then increases the expression of the autophagy-regulating kinase ULK1. This leads to increased mitophagy, as ULK1 is recruited to the mitochondria and activates FUNDC1 to promote DRP1-mediated mitochondrial fission that leads to mitochondrial interaction with the autophagosomal protein, MAP1LC3B-II [62].…”

“…Furthermore, genistein, a plant-derived compound, has recently been found to be an ESRRA agonist by small molecule screening [55,56,85], and improves diet-induced obesity by increasing energy expenditure, lipid catabolism via AMPK activation, and the serum TH concentration [86][87][88][89]. TH activates the PPARGC1A-ESRRA axis to increase mitochondrial biogenesis, activity, and turnover [62]. Although confirmatory studies need to be performed in ESSRA knockout mice, it is likely that ESRRA mediates many of genistein's beneficial effects on diet-induced obesity.…”