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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 TR? and TR? isoforms (TR?(-/-)?(-/-)). 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. MTP? 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.

SUBMITTER: Chocron ES 

PROVIDER: S-EPMC3385793 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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

Chocron E Sandra ES   Sayre Naomi L NL   Holstein Deborah D   Saelim Nuttawut N   Ibdah Jamal A JA   Dong Lily Q LQ   Zhu Xuguang X   Cheng Sheue-Yann SY   Lechleiter James D JD  

Molecular endocrinology (Baltimore, Md.) 20120508 7


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 shor  ...[more]

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