The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism

E. Sandra Chocron, Naomi L. Sayre, Deborah Holstein, Nuttawut Saelim, Jamal A. Ibdah, Lily Q. Dong, Xuguang Zhu, Sheue Yann Cheng, James D. Lechleiter

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 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.

Original languageEnglish (US)
Pages (from-to)1117-1128
Number of pages12
JournalMolecular Endocrinology
Issue number7
StatePublished - Jul 2012

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology


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