Thyroid Hormone Induces Ca-Mediated Mitochondrial Activation in Brown Adipocytes.

Thyroid hormones, including 3,5,3'-triiodothyronine (T), cause a wide spectrum of genomic effects on cellular metabolism and bioenergetic regulation in various tissues. The non-genomic actions of T have been reported but are not yet completely understood. Acute T 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 uniporter (MCU). T treatment depolarized the resting mitochondrial membrane potential (Ψ) but augmented oligomycin-induced hyperpolarization in brown adipocytes. Protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated by T, leading to the inhibition of autophagic degradation. Rapamycin, as an mTOR inhibitor, blocked T-induced autophagic suppression and UCP1 upregulation. T increases intracellular Ca concentration ([Ca]) in brown adipocytes. Most of the T effects, including mTOR activation, UCP1 upregulation, and OCR increase, were abrogated by intracellular Ca chelation with BAPTA-AM. Calmodulin inhibition with W7 or knockdown of MCU dampened T-induced mitochondrial activation. Furthermore, edelfosine, a phospholipase C (PLC) inhibitor, prevented T from acting on [Ca], UCP1 abundance, Ψ, and OCR. We suggest that short-term exposure of T induces UCP1 upregulation and mitochondrial activation due to PLC-mediated [Ca] elevation in brown adipocytes.