Thyroid hormone has a profound effect on cellular respiration. Abnormally high levels of this hormone accelerate respiration in conjunction with a general increase in metabolism while pathologically low amounts cause low levels of respiration with a general slowing of metabolic activity. The affect on respiration is primarily the result of changes in the expression of respiratory genes and modulation of inner membrane structure. This review focuses on the regulation of respiratory gene expression by thyroid hormone. Respiratory genes are encoded in both the nucleus and the mitochondrion, the products of which are required in stoichiometric amounts for proper assembly of the respiratory chain. Thyroid hormone influences the expression of a number of nuclear encoded respiratory genes at the level of mRNA and enhances expression of mitochondrially encoded respiratory genes. Therefore, thyroid hormone appears to affect gene regulation in two different cell compartments. The current evidence for a direct thyroid hormone/thyroid receptor regulation of these respiratory genes and possible indirect pathway(s) mediating the thyroid effect is discussed.
The respiratory deficient yeast nuclear mutant MK3 is defective in the synthesis of the mature transcripts of the mitochondrial COB and OX13 genes, which code for apocytochrome b and subunit I of cytochrome c oxidase, resp. Introns 3 and 4 of the COB transcript (bI3 and bI4) and intron 4 (aI4) of the OXI3 transcript can not be excised (Pillar et al. 1983a, b). When combined with mitochondrial genomes lacking introns bI1, bI2 and bI3, or lacking intron bI3 alone the mutant is respiratory competent. Thus, the non-excision of bI4 and aI4 turns out to be an indirect effect of the mutation. From a wild type yeast genebank a plasmid has been isolated with a 3.3 kb DNA insert, which complements the mutant. Subcloning experiments assigned the functional gene to a 1.6 kb HaeIII-Sau3A fragment. Hybridization experiments showed, that it is (i) a single copy gene, (ii) also present in strain D273-10B, containing the "short form" mitochondrial genome (lacking the COB introns bI1-bI3), and (iii) located on chromosome IX. The nuclear gene defective in mutant MK3, was named MRS1 (Mitochondrial RNA Splicing). The involvement of this nuclear gene in the excision of a single group I mitochondrial intron (bI3) of the COB transcript is discussed.
The structural gene for 5-aminolevulinate (ALA) synthase has been cloned and sequenced from the filamentous fungus Aspergillus nidulans using an oligonucleotide probe based on a highly conserved-amino-acid sequence found in ALA synthase genes of a wide range of species. The cloned gene, hemA, has a 5' untranslated mRNA of 92 nucleotides (nt) and one intron (64 nt). The deduced protein sequence (648 amino acids) shows 64% identity to the yeast ALA synthase in the C-terminal region of 453 amino acids. The N-terminal region is typical of ALA synthase proteins in that the specific amino-acid sequence is not conserved but consists of a "leader" region rich in basic amino acids, believed to be involved in mitochondrial targeting, followed by a stretch of largely hydrophobic residues which may allow interaction with the inner mitochondrial membrane. Under the conditions used the transcription of hemA was unaffected by dextrose repression, heat shock, or oxygen levels.
Translation of mitochondrial cytochrome b RNA in yeast requires the product of the nuclear gene CBS1, a 27.5 kDa soluble mitochondrial protein. In this paper we show that the CBS1 gene is located on chromosome IV immediately adjacent to COX9, the gene coding for cytochrome c oxidase subunit VIIa. CBS1 is transcribed as a very low abundant 900 b RNA. Transcription starts at a single position 101 bp upstream of the CBS1 initiation codon. At positions -39 to -27 of its leader sequence it contains a small open reading frame of 4 codons. By monitoring the beta-galactosidase activity of a CBS1/lacZ fusion construct we show that expression of CBS1 is subjected to regulation by oxygen and by glucose: the beta-galactosidase activity is elevated threefold in glycerol or galactose grown cells compared to that in glucose grown cells. A further threefold reduction of the activity is observed in anaerobically grown cells. In accordance with this result is the observation that the steady-state level of CBS1 mRNA of anaerobically grown cells is ninefold lower than that of aerobically cultured cells.
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