The Trifunctional Protein Mediates Thyroid Hormone Receptor-Dependent Stimulation of Mitochondria Metabolism

We previously demonstrated that the thyroid hormone, T3, acutely stimulates mitochondrial metabolism in a thyroid hormone receptor (TR)-dependent manner. T3 has also recently been shown to stimulate mitochondrial fatty acid oxidation (FAO). Here we report that TR-dependent stimulation of metabolism is mediated by the mitochondrial trifunctional protein (MTP), the enzyme responsible for long-chain FAO. Stimulation of FAO was significant in cells that expressed a nonnuclear amino terminus shortened TR isoform (sTR43) but not in adult fibroblasts cultured from mice deficient in both TRα and TRβ isoforms (TRα−/−β−/−). Mouse embryonic fibroblasts deficient in MTP (MTP−/−) did not support T3-stimulated FAO. Inhibition of fatty-acid trafficking into mitochondria using the AMP-activated protein kinase inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) or the carnitine palmitoyltransferase 1 inhibitor etomoxir prevented T3-stimulated FAO. However, T3 treatment could increase FAO when AMP-activated protein kinase was maximally activated, indicating an alternate mechanism of T3-stimulated FAO exists, even when trafficking is presumably high. MTPα protein levels and higher molecular weight complexes of MTP subunits were increased by T3 treatment. We suggest that T3-induced increases in mitochondrial metabolism are at least in part mediated by a T3-shortened TR isoform-dependent stabilization of the MTP complex, which appears to lower MTP subunit turnover.