PMID- 34445344 OWN - NLM STAT- MEDLINE DCOM- 20210915 LR - 20210915 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 16 DP - 2021 Aug 11 TI - Thyroid Hormone Induces Ca(2+)-Mediated Mitochondrial Activation in Brown Adipocytes. LID - 10.3390/ijms22168640 [doi] LID - 8640 AB - Thyroid hormones, including 3,5,3'-triiodothyronine (T(3)), cause a wide spectrum of genomic effects on cellular metabolism and bioenergetic regulation in various tissues. The non-genomic actions of T(3) have been reported but are not yet completely understood. Acute T(3) treatment significantly enhanced basal, maximal, ATP-linked, and proton-leak oxygen consumption rates (OCRs) of primary differentiated mouse brown adipocytes accompanied with increased protein abundances of uncoupling protein 1 (UCP1) and mitochondrial Ca(2+) uniporter (MCU). T(3) treatment depolarized the resting mitochondrial membrane potential (Psi(m)) but augmented oligomycin-induced hyperpolarization in brown adipocytes. Protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated by T(3), leading to the inhibition of autophagic degradation. Rapamycin, as an mTOR inhibitor, blocked T(3)-induced autophagic suppression and UCP1 upregulation. T(3) increases intracellular Ca(2+) concentration ([Ca(2+)](i)) in brown adipocytes. Most of the T(3) effects, including mTOR activation, UCP1 upregulation, and OCR increase, were abrogated by intracellular Ca(2+) chelation with BAPTA-AM. Calmodulin inhibition with W7 or knockdown of MCU dampened T(3)-induced mitochondrial activation. Furthermore, edelfosine, a phospholipase C (PLC) inhibitor, prevented T(3) from acting on [Ca(2+)](i), UCP1 abundance, Psi(m), and OCR. We suggest that short-term exposure of T(3) induces UCP1 upregulation and mitochondrial activation due to PLC-mediated [Ca(2+)](i) elevation in brown adipocytes. FAU - Nguyen, Minh-Hanh Thi AU - Nguyen MT AUID- ORCID: 0000-0002-7446-5607 AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. FAU - Ly, Dat Da AU - Ly DD AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. FAU - Nguyen, Nhung Thi AU - Nguyen NT AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. FAU - Qi, Xu-Feng AU - Qi XF AUID- ORCID: 0000-0002-5911-071X AD - Key Laboratory of Regenerative Medicine, Ministry of Education, Department of Developmental and Regenerative Biology, Jinan University, Guangzhou 510632, China. FAU - Yi, Hyon-Seung AU - Yi HS AD - Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Korea. FAU - Shong, Minho AU - Shong M AD - Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Korea. FAU - Cha, Seung-Kuy AU - Cha SK AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. FAU - Park, Sangkyu AU - Park S AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Precision Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. FAU - Park, Kyu-Sang AU - Park KS AUID- ORCID: 0000-0003-0322-9807 AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. AD - Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Gangwon-do, Korea. LA - eng GR - 2017R1A5A2015369/Ministry of Science and ICT, South Korea/ GR - 2020M3A9D8039920/Ministry of Science and ICT, South Korea/ PT - Journal Article DEP - 20210811 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 06LU7C9H1V (Triiodothyronine) RN - SY7Q814VUP (Calcium) SB - IM MH - Adipose Tissue, Brown/*drug effects/metabolism MH - Animals MH - Calcium/*metabolism/pharmacology MH - Calcium Signaling/drug effects/physiology MH - Cells, Cultured MH - Energy Metabolism/drug effects MH - Female MH - Membrane Potential, Mitochondrial/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Mitochondria/*drug effects/metabolism MH - Oxygen Consumption/drug effects MH - Triiodothyronine/*pharmacology PMC - PMC8395422 OTO - NOTNLM OT - Ca2+ signaling OT - brown adipose tissue (BAT) OT - mitochondria OT - thyroid hormone OT - uncoupling protein 1 (UCP1) COIS- The authors declare no conflict of interest. EDAT- 2021/08/28 06:00 MHDA- 2021/09/16 06:00 PMCR- 2021/08/11 CRDT- 2021/08/27 01:23 PHST- 2021/06/21 00:00 [received] PHST- 2021/08/06 00:00 [revised] PHST- 2021/08/07 00:00 [accepted] PHST- 2021/08/27 01:23 [entrez] PHST- 2021/08/28 06:00 [pubmed] PHST- 2021/09/16 06:00 [medline] PHST- 2021/08/11 00:00 [pmc-release] AID - ijms22168640 [pii] AID - ijms-22-08640 [pii] AID - 10.3390/ijms22168640 [doi] PST - epublish SO - Int J Mol Sci. 2021 Aug 11;22(16):8640. doi: 10.3390/ijms22168640.