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

Abstract

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.

Mice Lacking Thyroid Hormone Receptor β Show Enhanced Apoptosis and Delayed Liver Commitment for Proliferation after Partial Hepatectomy

“…Previous reports described anti-apoptotic effects of that TR activation in hepatocytes [30], [32], [33] and in other cell types; for example, pancreatic beta cells and oligodendrocytes [34], [35]. A likely mediator of pro-apoptotic activity in hypothyroidism or in the absence of TRs is increased oxidative stress due to the lack of T3 signaling [36], [37], [38].…”

Influence of levothyroxine treatment on serum levels of soluble Fas (CD95) and Fas Ligand (CD95L) in chronic autoimmune hypothyroidism

“…An increase in apoptosis in the optic lobe of the chick embryo [14], inhibition of multilayer formation of the osteoblastic cell line, MC3T3-E1, by promoting apoptosis after T3 treatment [15] and thyroid hormone regulation of apoptosis induced by retinoic acid in promyeloleukemic HL-60 cells [16] were reported. The function of triiodo-L-thyronine as an important anti-apoptotic factor in mouse hepatocytes [12], inhibition of apoptotic potency by activating thyroid hormone receptors in mitochondria [17], activation of anti-apoptotic myeloid cell leukemia 1 (an anti-apoptotic member of the B-cell lymphoma-2 family) by triiodothyronine [18] have been shown. Resveratrolinduced gene expression and apoptosis were inhibited more than 50% by physiological concentration of thyroid hormone in papillary and follicular thyroid cancer cells [19].…”

Histological and Histochemical Studies on the Early Developmental Stages of the Egyptian Toad <i>Bufo regularis</i> Reuss

“…This is followed by nuclear fragmentation and cytoplasmic con-densation associated with prolific budding to produce membrane-bound apoptotic bodies of varying sizes. As is the case in other solid tissues, the actual processes of budding is rarely observed, possibly viable cells engulf the condensing ones [22] [30]- [33].…”