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Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria

Nuttawut Saelim1, Deborah Holstein, Estrella S Chocron

  • 1Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

Apoptosis : an International Journal on Programmed Cell Death
|August 19, 2007
PubMed

Insights

Shortened thyroid hormone receptor isoforms (TRs) acutely inhibit apoptosis by targeting mitochondria. Thyroid hormone (T3) activates these TRs, increasing mitochondrial membrane potential and preventing cytochrome c release, thus regulating cell death.

Area of Science:

  • Mitochondrial Biology
  • Cell Signaling
  • Endocrinology

Background:

  • Shortened thyroid hormone receptor isoforms (TRs) were previously shown to target mitochondria.
  • These TRs can acutely modulate inositol 1,4,5 trisphosphate (IP3)-mediated Ca2+ signaling upon activation by 3,5,3'-tri-iodothyronine (T3).
  • This stimulation involves increased mitochondrial metabolism, independent of transcriptional activity.

Purpose of the Study:

  • To investigate the role of T3-bound TRs in regulating apoptosis.
  • To determine if T3-activated TRs inhibit apoptotic activity mediated by cytochrome c release.
  • To elucidate the mitochondrial localization and functional impact of TRs in T3-mediated apoptosis regulation.

Main Methods:

  • Modification of an apoptosis potency assay using Xenopus oocyte extracts and isolated liver nuclei.
  • Assessment of morphological changes in nuclei to quantify apoptotic potency.
  • Analysis of mitochondrial and cytosolic fractions for xTRbetaA1s expression and measurement of mitochondrial membrane potential.

Main Results:

  • T3 treatment significantly decreased apoptotic potency in oocyte extracts expressing xTRbetaA1s.
  • The anti-apoptotic effect of T3 was dependent on xTRbetaA1s expression in the mitochondrial fraction.
  • T3 treatment increased the membrane potential of isolated mitochondria from xTRbetaA1s-expressing oocytes, but not wildtype controls.

Conclusions:

  • T3-bound shortened thyroid hormone receptor isoforms (xTRbetaA1s) acutely inhibit apoptosis.
  • This inhibition is mediated by regulating cytochrome c release in a membrane potential-dependent manner.
  • Thyroid hormone receptors located within mitochondria are key players in the acute regulation of apoptosis.

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