cytochromes-c1 and Hypothyroidism

Thyroid hormone regulates the in vivo expression of a selected set of rat nuclear genes encoding mitochondrial inner membrane proteins. Certain mRNAs, such as that for cytochrome c1, are increased as much as 20-50-fold, while others, such as core protein 1 of Complex III and the F1-ATPase beta-subunit do not respond. The promoter region of human cytochrome c1 also supports thyroid hormone induction of a reporter gene in transient transfection experiments. Thus, thyroid hormone regulates only selected genes, even for subunits within the same complex and in widely varying species. By contrast, growth activation of quiescent NIH3T3 cells, a second paradigm used for stimulating mitochondrial biogenesis, does not increase cytochrome c1 mRNA but does increase F1-ATPase beta-subunit mRNA. These findings suggest that nuclear OXPHOS genes are not necessarily expressed in a coordinated manner, and that multiple regulatory circuits might exist which are linked to different physiological stimuli. Analysis of the promoters of several OXPHOS genes reveals a great diversity and heterogeneity of transfactor binding elements. No single regulatory feature exists which could account for a coordinated expression of all OXPHOS genes. The potential diversity for regulating expression of nuclear OXPHOS genes raises the possibility for the existence of disease states linked to regulatory defects.

Topics: 3T3 Cells; Animals; Base Sequence; Blotting, Northern; Cell Division; Cell Nucleus; Cytochromes c1; Gene Expression Regulation; Genetic Variation; Humans; Hypothyroidism; Macromolecular Substances; Membrane Proteins; Mice; Mitochondria; Mitochondria, Liver; Molecular Sequence Data; Oxidative Phosphorylation; Promoter Regions, Genetic; Proton-Translocating ATPases; Rats; Recombinant Proteins; RNA, Messenger; Transcription, Genetic; Transfection; Triiodothyronine

The effects of L-T3 and several analogues on mitochondrial parameters were determined in hypothyroid rats. These parameters include the 24 hour hormone-induced changes in the bc1 complex and in the inner membrane's proton permeability. L-T3, and all analogues except rT3, increased mitochondrial ubiquinone to euthyroid levels. L-T3, D-T3 and 3'IpT2 but not rT3, Triac, Triprop, or Dimit, altered the bypass respiration in the bc1 complex. L-T3, D-T3, Triac, 3'IpT2, and Triprop, but not rT3 or Dimit, increased the membrane's proton permeability. Actinomycin D did not prevent the increase in mitochondrial ubiquinone or the permeability change. The results show the selective thyromimetic properties of the analogues and that some of the mitochondrial changes do not require protein synthesis.

Topics: Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cytochromes c1; Dactinomycin; Electron Transport; Glycerolphosphate Dehydrogenase; Hypothyroidism; Intracellular Membranes; Liver; Male; Mitochondria; Oxygen Consumption; Permeability; Proton Pumps; Rats; Rats, Sprague-Dawley; Triiodothyronine; Triiodothyronine, Reverse; Ubiquinone

Thyroid hormone is one of the few known physiological regulators of mammalian mitochondrial biogenesis. Although it exerts a global effect on biogenesis, it does so by regulating the expression of a limited number of unidentified mitochondrial proteins. We have investigated these hormone-regulated proteins in rat liver. Hormone injection induced a 30-fold increase in the levels of cytochrome-c1 mRNA after 3 d. In addition, the mRNA for the growth-activated adenine-nucleotide translocator, ANT2, was increased 13-fold and that for the ATPase N,N'-dicyclohexylcarbodiimide-binding protein increased 4-5-fold. Mitochondrial transcripts of cytochrome-oxidase subunit I also increased. No changes were found in the mRNA levels for the F1-ATPase beta-subunit or cytochrome oxidase IV. A single low dose of triiodothyronine induces rapid increases in cytochrome-c1 and ANT2 mRNA species which parallel changes in the activity of the hormone-responsive malic enzyme, but are earlier than other mitochondrial biogenetic events. These data strengthen the view that thyroid hormone regulates synthesis of specific components within each respiratory-chain complex and that these products apparently play key roles in inner-membrane biogenesis and assembly. The significance of ANT2 induction is also discussed with respect to the rapid respiratory response induced by thyroid hormone.

Topics: Adenosine Triphosphatases; Animals; Cell Nucleus; Cytochromes c1; Electron Transport Complex IV; Hypothyroidism; Macromolecular Substances; Malate Dehydrogenase; Male; Mitochondria, Liver; Mitochondrial ADP, ATP Translocases; Rats; Rats, Inbred Strains; RNA, Messenger; Transcription, Genetic; Triiodothyronine