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Sci Signal. 2018 Jun 26;11(536). pii: eaam5855. doi: 10.1126/scisignal.aam5855.

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

Author information

1
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore. paul.yen@duke-nus.edu.sg singhbrijeshk@duke-nus.edu.sg.
2
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore.
3
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
4
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Center for Life Sciences, 330 Brookline Avenue, Boston, MA 02215, USA.
5
Department of Internal Medicine, Enshu Hospital, Hamamatsu, Shizuoka 430-0929, Japan.
6
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, C238A Levine Science Research Center, Durham, NC 27710, USA.
7
Department of Anatomy, Yong Loo Lin School of Medicine, NUS, Singapore.
8
Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada.
9
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.

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 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.

PMID:
29945885
DOI:
10.1126/scisignal.aam5855

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