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 (TR_α^-/-β^-/-). Mouse embryonic fibroblasts deficient in MTP (MTP^-/-) did not support T₃-stimulated FAO. Inhibition of fatty-acid trafficking into mitochondria usingthe AMP-activated protein kinase inhibitor6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) orthe 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.