Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria.
We recently reported that shortened thyroid hormone receptor isoforms (TRs) can target mitochondria and acutely modulate inositol 1,4,5 trisphosphate (IP3)-mediated Ca2+ signaling when activated by thyroid hormone 3,5,3'-tri-iodothyronine (T3). Stimulation occurs via an increase in mitochondrial metabolism that is independent of transcriptional activity. Here, we present evidence that T3-bound xTRbetaA1s inhibit apoptotic activity mediated by cytochrome c release. An assay for apoptotic potency was modified to measure the ability of Xenopus oocyte extracts to induce morphological changes in isolated liver nuclei. Apoptotic potency was significantly decreased when oocyte extract was prepared from xTRbetaA1 expressing oocytes and treated with T3. The ability of T3 treatment to inhibit apoptosis was dependent on the expression of xTRbetaA1s in the mitochondrial fraction, not in the cytosolic fraction. T3 treatment also increased the membrane potential of isolated mitochondria prepared from oocytes expressing xTRbetaA1s but not from wildtype controls. We conclude that T3 acutely regulates cytochrome c release in a potential dependent manner by activating TRs located within mitochondria.
Saelim
Nuttawut
N
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Holstein
Deborah
D
Chocron
Estrella S
ES
Camacho
Patricia
P
Lechleiter
James Donald
JD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*; D014982:Xenopus laevis
D005456:Fluorescent Dyes; D008024:Ligands; D020033:Protein Isoforms; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine