The mitochondrion, the cell's Pandora's box, contains potentially harmful proteins that it keeps hidden away. Activation of these harmful proteins sets in motion programmed cell death (apoptosis) pathways that result in the demise of the cell. In many of these pathways, permeabilization of mitochondrial membranes is a critical event that results in release (from the mitochondrial intermembrane space) of various molecules that are crucial for apoptosis. Such molecules include enzymes called pro-caspases, cytochrome c (a caspase activator), Smac/Diablo (a caspase coactivator)(1), and an apoptosis-inducing factor, which activates the nucleases that chop up DNA into small fragments. Now, on page 1159 of this issue, Li and colleagues (2) report the tantalizing discovery that a potential proapoptotic transcription factor, TR3 (also called Nur77 or NGFIB), normally present in the nucleus, can move to mitochondria where it triggers membrane permeabilization and apoptotic cell death.

Like other proteins in the steroid/thyroid receptor superfamily, TR3 is a transcription factor with a central zinc finger DNA binding domain flanked by transactivation domains. In contrast to other steroid receptors, however, the endogenous ligand of TR3 (which is predicted to interact with the carboxyl-terminal half of the receptor) has not yet been identified, making TR3 an “orphan” receptor. TR3 forms homodimers with itself and heterodimers with other proteins from the same family, in particular with the 9-cis-retinoic acid receptor (RXR). The TR3 DNA binding domain interacts with a specific DNA octamer sequence, the Nur77/NGFIB-binding response element (NBRE), and, when in a heterodimer with RXR, also with the retinoic acid response element. Usually, TR3 (and RXR) are imported into the nucleus after their synthesis in the cytoplasm. This implies that most if not all of TR3's activity is in the nucleus. Under specific circumstances, however, TR3 can be exported back to the cytoplasm. This halts its transcriptional activity (2) and may also suppress that of RXR, which accompanies TR3 back to the cytoplasm (3).