A variant form of the nuclear triiodothyronine receptor c-ErbA alpha 1 plays a direct role in regulation of mitochondrial RNA synthesis

In earlier research, we identified a 43-kDa c-ErbA alpha 1 protein (p43) in the mitochondrial matrix of rat liver. In the present work, binding experi ments indicate that p43 displays an affinity for triiodothyronine (T3) simi lar to that of the T3 nuclear receptor. Using in organello import experimen ts, we found that p43 is targeted to the organelle by an unusual process si milar to that previously reported for MTF1, a yeast mitochondrial transcrip tion factor. DNA-binding experiments demonstrated that p43 specifically bin ds to four mitochondrial DNA sequences with a high similarity to nuclear T3 response elements (mt-T3REs). Using in organello transcription experiments , we observed that p43 increases the levels of both precursor and mature mi tochondrial transcripts and the ratio of mRNA to rRNA in a T3-dependent man ner. These events lead to stimulation of mitochondrial protein synthesis. I n transient-transfection assays with reporter genes driven by the mitochond rial D loop or two mt-T3REs located in the D loop, p43 stimulated reporter gene activity only in the presence of T3. All these effects were abolished by deletion of the DNA-binding domain of p43. Finally p43 overexpression in QM7 cells increased the levels of mitochondrial mRNAs, thus indicating tha t the in organello influence of p43 was physiologically relevant. These dat a reveal a novel hormonal pathway functioning within the mitochondrion, inv olving a truncated form of a nuclear receptor acting as a potent mitochondr ial T3-dependent transcription factor.