Gating of the mitochondrial permeability transition pore by thyroid hormone

The calorigenic-thermogenic activity of thyroid hormone (T3) has long been ascribed to uncoupling of mitochondrial oxidative phosphorylation. However, the mode of action of T3 in promoting mitochondrial proton leak is still unresolved. Mitochondrial uncoupling by T3 is reported here to be transduced in vivo in rats and in cultured Jurkat cells by gating of the mitochondrial permeability transition pore (PTP). T3-induced PTP gating is shown here to be abrogated in inositol 1,4,5-trisphosphate (IP³) receptor 1 (IP³R1) ^-/- cells, indicating that the endoplasmic reticulum IP³R1 may serve as upstream target for the mitochondrial activity of T3. IP ₃R1 gating by T3 is due to its increased expression and truncation into channel-only peptides, resulting in IP3-independent Ca²⁺ efflux. Increased cytosolic Ca²⁺ results in activation of protein phosphatase 2B, dephosphorylation and depletion of mitochondrial Bcl2 (S70), and increase in mitochondrial free Bax leading to low-conductance PTP gating. The T3 transduction pathway integrates genomic and nongenomic activities of T3 in regulating mitochondrial energetics and may offer novel targets for thyromimetics designed to modulate energy expenditure.