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 journalArticle

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Abstract

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
Volume26
Issue number7
DOIs
StatePublished - Jul 2012

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Mitochondrial Trifunctional Protein
Thyroid Hormone Receptors
Mitochondria
Fatty Acids
Proteins
Protein Isoforms
AMP-Activated Protein Kinases
Protein Subunits
Triiodothyronine
Fibroblasts
Carnitine O-Palmitoyltransferase
Molecular Weight

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism. / Sandra Chocron, E.; Sayre, Naomi L.; Holstein, Deborah; Saelim, Nuttawut; Ibdah, Jamal A.; Dong, Lily Q; Zhu, Xuguang; Cheng, Sheue Yann; Lechleiter, James D.

In: Molecular Endocrinology, Vol. 26, No. 7, 07.2012, p. 1117-1128.

Research output: Contribution to journalArticle

Sandra Chocron, E. ; Sayre, Naomi L. ; Holstein, Deborah ; Saelim, Nuttawut ; Ibdah, Jamal A. ; Dong, Lily Q ; Zhu, Xuguang ; Cheng, Sheue Yann ; Lechleiter, James D. / The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism. In: Molecular Endocrinology. 2012 ; Vol. 26, No. 7. pp. 1117-1128.
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