title: The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism.
abstract: We previously demonstrated that the thyroid hormone, T(3), acutely stimulates mitochondrial metabolism in a thyroid hormone receptor (TR)-dependent manner. T(3) 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 (sTR(43)) 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 T(3)-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 T(3)-stimulated FAO. However, T(3) treatment could increase FAO when AMP-activated protein kinase was maximally activated, indicating an alternate mechanism of T(3)-stimulated FAO exists, even when trafficking is presumably high. MTPα protein levels and higher molecular weight complexes of MTP subunits were increased by T(3) treatment. We suggest that T(3)-induced increases in mitochondrial metabolism are at least in part mediated by a T(3)-shortened TR isoform-dependent stabilization of the MTP complex, which appears to lower MTP subunit turnover.
authors.affiliation: Departments Of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
authors.forename: E Sandra
authors.initials: ES
authors.lastname: Chocron
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Sayre
authors.forename: Deborah
authors.initials: D
authors.lastname: Holstein
authors.forename: Nuttawut
authors.initials: N
authors.lastname: Saelim
authors.forename: Jamal A
authors.initials: JA
authors.lastname: Ibdah
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004789:Enzyme Activation; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency / Q000378:metabolism*; D010084:Oxidation-Reduction; D021381:Protein Transport; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D004852:Epoxy Compounds; D005227:Fatty Acids; D009097:Multienzyme Complexes; D011720:Pyrazoles; D011743:Pyrimidines; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; C516138:dorsomorphin; D063991:Mitochondrial Trifunctional Protein; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases; C054207:etomoxir