Skip to content. | Skip to navigation

Personal tools

Sections
You are here: Home / Research Teams / F. FLAMANT - Functional genomics of thyroid signaling / Publications / Publications IGFL / Thyroid hormone receptor and ERRalpha coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function.

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

Brijesh K Singh, Rohit A Sinha, Madhulika Tripathi, Arturo Mendoza, Kenji Ohba, Jann AC Sy, Sherwin Y Xie, Jin Zhou, Jia P Ho, Ching-Yi Chang, Yajun Wu, Vincent Giguere, Boon-Huat Bay, Jean-Marc Vanacker, Sujoy Ghosh, Karine Gauthier, Anthony N Hollenberg, Donald P McDonnell, and Paul M Yen (2018)

Sci Signal, 11(536).

Thyroid hormone receptor beta1 (THRB1) and estrogen-related receptor alpha (ESRRA; also known as ERRalpha) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptomeand 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 beta-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 PGC1alpha). Moreover, TH induced mitochondrial biogenesis, fission, and mitophagy in an ESRRA-dependent manner. TH also inducedthe expression of the autophagy-regulating kinase ULK1 through ESRRA, which thenpromoted 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 expressionand 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.

 
automatic medline import

Document Actions