Mobilization of Mg²⁺from Rat Heart and Liver Mitochondria following the Interaction of Thyroid Hormone with the Adenine Nucleotide Translocase

Abstract

The in vitro addition of thyroid hormone to isolated rat heart or liver mitochondria induces the extrusion of approximately 2-4 nmol Mg2+/mg protein from both mitochondria preparations. The mobilization of Mg2+ is not accompanied by extrusion of matrix ATP or K+, or by mitochondria swelling, thus excluding that the phenomenon occurs through the nonspecific opening of the mitochondrial permeability transition pore. Moreover, the Mg2+ extrusion is completely prevented by bongkrekic acid, a membrane-permeant inhibitor of the adenine nucleotide translocase (AdNT), and by cyclosporine, which has also been reported to inhibit AdNT in a bongkrekate-like manner, operating at the matrix site of the translocase. By contrast, atractyloside, another specific inhibitor of AdNT that operates at the cytosolic site of the AdNT, only partially affects the Mg2+ mobilization (< 30% inhibition). These findings and the binding of 125I-labeled thyroid hormone to both the dimeric and monomeric moiety of AdNT support the hypothesis that AdNT can operate as a specific receptor for thyroid hormone in the mitochondria, and suggest that thyroid hormone operates at the matrix site of the translocase. In addition, these observations may imply that some of the so called "nongenomic effects" exerted by thyroid hormone on mitochondrial metabolism could occur through changes in the matrix content of Mg2+.

Direct action of T3on phosphorylation potential in the sheep heart in vivo

“…However, deficiency in direct T 3 stimulation of ADP/ ATP exchange could explain in part the increase in ADP associated with epinephrine infusion in the thyroidectomized sheep. This consideration stems from reports from several research groups identifying specific T 3 -binding activity in the inner mitochondrial membrane in association with rapid T 3 enhancement of ADP/ATP exchange efficiency (27,42,48,49 (27) demonstrated that reduced ADP/ATP exchange efficiency in liver mitochondria isolated under hypothyroid conditions can be normalized to euthyroid levels within 15 min of T 3 exposure provided either in vivo or in vitro. The precise mechanism for immediate T 3 action on liver mitochondria ANT remains controversial, but some studies implicate T 3 allosteric modification of an ADP-ribosyl transferase, which covalently modifies ANT, as opposed to direct T 3 binding to ANT (27).…”

Nontranscriptional modulation of intracellular Ca2+ signaling by ligand stimulated thyroid hormone receptor

“…Sterling (1986Sterling ( , 1991 initially suggested that the adenine nucleotide translocator (ANT) bound to T 3 with high affinity. Romani et al (1996) also suggested that thyroid hormone had its specific mitochondrial target site at the matrix side of ANT. They found that bongkrekic acid, a membrane-permeant inhibitor of ANT, blocked a thyroid hormone-induced release of Mg 2ϩ from mitochondria.…”

Physiological and Molecular Basis of Thyroid Hormone Action

“…Sterling and colleagues (483)(484)(485) reported the presence of specific mitochondrial receptors over 20 years ago and thus provided an attractive unifying model for T 3 effects on mitochondrial activity and cellular energy state. There is some evidence that the site of TH action in mitochondria is the adenine nucleotide translocase of the inner mitochondrial membrane (428,483). However, this work has been difficult to confirm as there are conflicting reports in the literature on the site of TH action in mitochondria (116, 185,276).…”