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

Prior research has shown that thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA) influence mitochondrial function. However, the specific interplay between these two receptors in regulating mitochondrial dynamics remained unclear. Established knowledge includes the role of THRB1 in thyroid hormone signaling and ESRRA in metabolic gene regulation. No prior work had resolved how these two receptors coordinate mitochondrial processes like fission, biogenesis, and mitophagy. This gap motivated the current investigation into their combined regulatory mechanisms. The study aimed to clarify how THRB1 and ESRRA together influence mitochondrial pathways. Prior studies lacked a comprehensive view of co-regulated genes and downstream effects. The absence of data on how THRB1 and ESRRA interact to control mitochondrial turnover created a need for this work. Understanding these interactions could provide new insights into metabolic disease mechanisms.

The aim of this study was to determine how thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA) interact to regulate mitochondrial processes. The researchers focused on identifying co-regulated genes and signaling pathways influenced by both receptors. They sought to understand how thyroid hormone (TH) affects mitochondrial fission, mitophagy, and biogenesis. The motivation stemmed from the need to clarify the functional relationship between THRB1 and ESRRA in mitochondrial dynamics. Previous studies had not fully explained the interplay between these two receptors. The study proposed to use transcriptome and ChIP-seq analyses to uncover shared regulatory mechanisms. The goal was to assess how TH activates ESRRA via THRB1 and how this affects mitochondrial function. The findings could help explain how hormonal signals influence mitochondrial quality control.

The study used transcriptome and ChIP-seq analyses to identify genes co-regulated by THRB1 and ESRRA. Researchers examined gene expression patterns in response to thyroid hormone (TH) treatment. They assessed the role of THRB1 in regulating ESRRA expression and activity. The team used siRNA knockdown to test the effects of ESRRA, ULK1, DRP1, and FUNDC1 on mitochondrial processes. They measured changes in mitochondrial fission, mitophagy, and OXPHOS activity. The study also evaluated the interaction between FUNDC1 and MAP1LC3B-II in autophagy. Researchers analyzed how TH activates ULK1 through ESRRA and how this influences DRP1-mediated fission. The methods included functional assays to confirm the role of these proteins in TH-induced mitochondrial turnover.

Thyroid hormone (TH) increased ESRRA expression and activity in a THRB1-dependent manner. TH induced mitochondrial biogenesis, fission, and mitophagy through ESRRA. The hormone also elevated ULK1 expression, which activated DRP1-mediated fission. ULK1 promoted FUNDC1 interaction with MAP1LC3B-II to induce mitophagy. Knockdown of ESRRA, ULK1, DRP1, or FUNDC1 reduced TH-induced mitophagy and OXPHOS. Co-regulated genes included those involved in OXPHOS, the TCA cycle, and fatty acid β-oxidation. THRB1 and ESRRA together controlled mitochondrial turnover via the PPARGC1A-ESRRA-ULK1 pathway. These findings suggest that TH effects on mitochondria are mediated through ESRRA activation.

The authors propose that TH effects on mitochondrial dynamics are mediated through THRB1 and ESRRA. They suggest that TH activates ESRRA via THRB1 and PPARGC1A to regulate mitochondrial fission and mitophagy. The study shows that ESRRA and ULK1 are essential for TH-induced mitochondrial turnover. The findings indicate that ESRRA, ULK1, DRP1, and FUNDC1 work together to promote mitophagy. The authors suggest that hormonal or pharmacologic activation of ESRRA could improve mitochondrial quality. The study supports a model where THRB1 and ESRRA co-regulate mitochondrial pathways. The data imply that TH signaling through ESRRA is crucial for mitochondrial homeostasis. These conclusions are based on the observed effects of TH and gene knockdown experiments.