The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism.
Mol Endocrinol
; 26(7): 1117-28, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22570332
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 TRß isoforms (TRα(-/-)ß(-/-)). 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thyroid Hormones
/
Thyroid Hormone Receptors alpha
/
Thyroid Hormone Receptors beta
/
Mitochondria
/
Multienzyme Complexes
Limits:
Animals
Language:
En
Journal:
Mol Endocrinol
Journal subject:
BIOLOGIA MOLECULAR
/
ENDOCRINOLOGIA
Year:
2012
Type:
Article
Affiliation country:
United States