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 (IP(3)) receptor 1 (IP(3)R1)(-/-) cells, indicating that the endoplasmic reticulum IP(3)R1 may serve as upstream target for the mitochondrial activity of T3. IP(3)R1 gating by T3 is due to its increased expression and truncation into channel-only peptides, resulting in IP(3)-independent Ca(2+) efflux. Increased cytosolic Ca(2+) 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.
Yehuda-Shnaidman
Einav
E
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
Kalderon
Bella
B
Azazmeh
Narmen
N
Bar-Tana
Jacob
J
D000818:Animals; D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D019169:Jurkat Cells; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D017931:DNA Primers; D053496:Inositol 1,4,5-Trisphosphate Receptors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D014284:Triiodothyronine; D019703:Calcineurin