Thyroid hormone and dexamethasone increase the levels of a messenger ribonucleic acid for a mitochondrially encoded subunit but not for a nuclear-encoded subunit of cytochrome c oxidase.
The nuclear genome is the primary locus of activity for thyroid hormone and dexamethasone; however, one well described secondary effect of treatment with these hormones is increased mitochondrial respiratory activity. To examine the mechanism of the increase in respiration, we have treated a rat hepatoma cell line, HTC cells, with thyroid hormone and dexamethasone and measured their effects on the activity of a respiratory chain enzyme and on mitochondrial (mt) RNA and mtDNA levels. Thyroid hormone, but not dexamethasone, increased cytochrome c oxidase activity in HTC cells; the increase in activity was nearly 2-fold over control values. To determine whether this increased activity was the result of coordinate increases in expression of nuclear and cytoplasmic genes for this enzyme, we measured changes in the levels of messenger RNAs for both nuclear and mitochondrially encoded cytochrome oxidase subunits. Treatment of HTC cells with thyroid hormone and/or dexamethasone resulted in 3- to 4-fold increases in the levels of several RNAs encoded in the mt genome, including subunit II of cytochrome c oxidase. In contrast, this treatment had no effect on the messenger RNA encoding a nuclear subunit of this same enzyme. Neither of these hormones had any effect on cell number or on the level of mtDNA. Dose response and time course of thyroid hormone and dexamethasone administration on mtRNA levels were consistent with these hormones acting through their nuclear hormone receptors. Increased expression of the mt genome by alteration of transcription or RNA stability is a likely candidate for a mechanism by which these hormones can regulate mitochondrial activity.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
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Van Itallie
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003573:Cytochrome b Group / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D051381:Rats; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D003573:Cytochrome b Group; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S; D014284:Triiodothyronine; D012313:RNA; D003907:Dexamethasone; D003576:Electron Transport Complex IV