Thyroid Hormone Induces Ca(2+)-Mediated Mitochondrial Activation in Brown Adipocytes

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 (Ψ(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, Ψ(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.