REGULATION BY THYROID-HORMONE OF NUCLEAR AND MITOCHONDRIAL GENES ENCODING SUBUNITS OF CYTOCHROME-C-OXIDASE IN RAT-LIVER AND SKELETAL-MUSCLE

Biogenesis of mitochondria involves the expression of genes located on nuclear chromosomes as well as on mitochondrial DNA. We studied the coordination of the two genomes by measuring transcript levels for nuclear (IV, Va, and VIc) and mitochondrial (II and III) subunits of cytochrome-c oxidase after altering the mitochondrial content of rat muscle and liver by altering the thyroid state of the animals. Tissue levels of these mRNAs were generally decreased in hypothyroid animals and were up-regulated again after thyroid hormone (T3) treatment. However, significant increases in the levels of all nuclear transcripts were observed in the liver 24 h after T3 treatment, but were delayed or remained unaltered (VIc) in muscle. In contrast, levels of mitochondrial transcripts were elevated early in muscle and late in liver. The abundance of the corresponding polypeptides, which were analyzed by immunoblotting, changed in direction and magnitude according to the changes in their mRNAs, indicating pretranslational control. We conclude that the two genomes are regulated by T3 not through a common coordinating mechanism, but via two separate pathways, which respond to T3 with tissue-specific kinetics. S1-nuclease protection analysis showed that probably only one transcript for subunit VIc is present in both tissues, thus excluding the possibility that the tissue-specific response is due to the expression of two isogenes. The abundance of mitochondrial DNA was unaltered despite the observed changes in mitochondrial transcripts, indicating that mitochondrial gene expression is regulated by transcriptional mechanisms and not by gene dosage as has been postulated by others.