Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function.
Brijesh Kumar SinghRohit A SinhaMadhulika TripathiArturo MendozaKenji OhbaJann A C SySherwin Y XieJin ZhouJia Pei HoChing-Yi ChangYajun WuVincent GiguèreBoon-Huat BayJean-Marc VanackerSujoy GhoshKarine GauthierAnthony N HollenbergDonald P McDonnellPaul M YenPublished in: Science signaling (2018)
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.
Keyphrases
- oxidative stress
- poor prognosis
- diabetic rats
- binding protein
- cell death
- gene expression
- high glucose
- genome wide
- high throughput
- mass spectrometry
- signaling pathway
- adipose tissue
- climate change
- dna methylation
- metabolic syndrome
- drug delivery
- hydrogen peroxide
- long non coding rna
- endothelial cells
- molecular dynamics simulations
- cancer therapy
- amino acid
- high density
- liquid chromatography
- reactive oxygen species
- tyrosine kinase
- bone mineral density
- endoplasmic reticulum