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 xTR _βA1s 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 xTR_βA1 expressing oocytes and treated with T ₃. The ability of T₃ treatment to inhibit apoptosis was dependent on the expression of xTR_βA1s in the mitochondrial fraction, not in the cytosolic fraction. T₃ treatment also increased the membrane potential of isolated mitochondria prepared from oocytes expressing xTR_βA1s but not from wildtype controls. We conclude that T ₃ acutely regulates cytochrome c release in a potential dependent manner by activating TRs located within mitochondria.