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Modulation of Mitochondrial Transition Pore Components by Thyroid Hormone

Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel

Address all correspondence and requests for reprints to: Dr. Jacob Bar-Tana, Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel. E-mail: bartanaj{at}cc.huji.ac.il.

Thyroid hormone (TH) modulates metabolic efficiency by controlling the coupling of mitochondrial oxidative phosphorylation. However, its uncoupling mode of action is still enigmatic. Treatment of Jurkat or GH₃ cells with T₃ is reported here to result in limited, Cyclosporin A-sensitive mitochondrial depolarization, conforming to low conductance gating of the mitochondrial transition pore (MTP). MTP protein components induced by T₃ treatment were verified in T₃-treated and hypothyroid rat liver as well as in Jurkat cells. T₃ treatment resulted in increase in mitochondrial Bax and Bak together with decreased mitochondrial Bcl2. T₃-induced mitochondrial depolarization was aborted by overexpression of Bcl2. In contrast to Bax-Bcl2 family proteins, some other MTP components were either not induced by T₃ (e.g. voltage-dependent anion channel) or were induced, but were not involved in Cyclosporin A-sensitive MTP gating (e.g. Cyclophilin D and adenine nucleotide translocase-2) Hence, TH-induced mitochondrial uncoupling may be ascribed to low conductance MTP gating mediated by TH-induced increase in mitochondrial proapoptotic combined with a decrease in mitochondrial antiapoptotic proteins of the Bax-Bcl2 family.

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