Gene/Protein Disease Symptom Drug Enzyme Compound
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We have investigated the effect of doxorubicin (Adriamycin) on the yeast Saccharomyces cerevisiae. Drug treatment was found to be cytotoxic to wild-type strains, in a concentration-dependent manner, whereas a petite mutant lacking the cytochrome oxidase (EC 1.9.3.1) subunit IV gene was resistant to doxorubicin. Transformation of the doxorubicin-resistant mutant with a yeast in vivo expression vector harboring the cytochrome oxidase subunit IV gene restored both respiration and sensitivity to doxorubicin. Another petite strain, with a mutation in the mitochondrial adenine nucleotide translocator (pet9), did not display doxorubicin resistance. However, in contrast to the subunit IV mutant, it possesses a functional respiratory chain. We also compared the cytotoxic effect of doxorubicin with those of daunorubicin and mitoxantrone in yeast. We found comparable levels of cytotoxicity for doxorubicin and daunorubicin, which were significantly greater than that for mitoxantrone. Finally, we constructed a yeast strain that overexpresses manganese superoxide dismutase (EC 1.15.1.1), an antioxidant enzyme present in mitochondria. Overexpression of manganese superoxide dismutase protected significantly against doxorubicin and daunorubicin cytotoxicity but only slightly against mitoxantrone cytotoxicity. Collectively, our results provide direct in vivo evidence that superoxide radicals participate in doxorubicin- and daunorubicin-induced cytotoxicity in yeast. Furthermore, these results indicate that mitochondrial respiration is a crucial factor in anthracycline, and perhaps mitoxantrone, cytotoxicity in yeast.
Mol Pharmacol 1994 Dec
PMID:Doxorubicin, daunorubicin, and mitoxantrone cytotoxicity in yeast. 780 47

In phylogenetic trees based on comparison of nuclear small subunit rRNA sequences, Acanthamoeba castellanii (an amoeboid protozoon) is positioned near the base of the radiation leading to the animals, fungi and plants. However, the specific affiliation of this protist with the major multicellular lineages of eukaryotes is currently uncertain. To further explore the evolutionary position of A. castellanii, we have determined the complete primary sequence of its mitochondrial genome. We find that the circular mtDNA (41,591 bp; 70.6% A+T) encodes two rRNAs (small subunit and large subunit), 16 tRNAs and 33 proteins (17 subunits of the respiratory chain and 16 ribosomal proteins). As well, this genome contains eight open reading frames (ORFs) larger than 60 codons and of undefined function. Two of these ORFs (orf124 and orf142) have homologs in other mtDNAs ("orf25" and "orfB", respectively), three are unique to A. castellanii mtDNA (orf83, orf115 and orf349), and three are intronic ORFs. Among notable features of A. castellanii mtDNA are the following: (1) Genes and ORFs are all encoded on the same strand and are tightly packed, with only 6.8% of the total sequence not having an evident coding function and intergenic spacer sequences ranging from only 1 to 616 bp (average 64 bp). Ten pairs of protein-coding genes overlap by up to 38 bp and two subunits of cytochrome oxidase (COX1 and COX2) are specified by a single continuous ORF. (2) Only three introns, all group I and each containing a free-standing ORF, are present; these are localized in the 3'-half of the large subunit rRNA gene. (3) The genome encodes fewer than the minimal number of tRNA species required to support mitochondrial protein synthesis, suggesting that additional tRNAs are imported from the cytosol into A. castellanii mitochondria. Of the 16 tRNAs specified by A. castellanii mtDNA (one with an 8-nucleotide anticodon loop), 13 have been shown or are predicted to undergo a novel form of RNA editing within the acceptor stem. (4) A modified genetic code is used in which UGA specifies tryptophan. (5) Repeated sequences and obvious small sequence motifs that might represent regulatory elements are absent. In overall size, gene content and organizational pattern, A. castellanii mtDNA most closely resembles the mtDNA of the chlorophycean alga Prototheca wickerhamii (55,326 bp; 74.2% A+T), but is quite different in these respects from the mtDNA of Chlamydomonas reinhardtii (15,758 bp; 54.8% A+T), another chlorophycean alga, as well from characterized animal and fungal mitochondrial genomes.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Biol 1995 Feb 03
PMID:The mitochondrial DNA of the amoeboid protozoon, Acanthamoeba castellanii: complete sequence, gene content and genome organization. 784 23

Recent studies show that patients presenting with cytochrome oxidase (COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) may be an important regulator of both transcription and replication of mtDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA (rho 0) or temporarily depleted by treatment with dideoxycytidine (ddC), and in tissue from three patients with mtDNA depletion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by Western blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nuclear probes was measured by dual labelling of dot blots. The ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle in the three patients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-mtTFA roughly paralleled mtDNA levels. Similarly, treatment of rho 0 cell lines with ddC induced a reduction in mtDNA as well as h-mtTFA protein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an increase in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h-mtTFA expression may be regulated by a feedback mechanism initiated by MtDNA Depletion.
Hum Mol Genet 1994 Oct
PMID:Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. 784 99

Ultrastructural changes of mitochondria and histochemical changes of the cytochrome oxidase of mitochondria during global ischemia and in reperfused rat heart were observed under transmission electron microscope. The ultrastructural changes of mitochondria were evaluated by scoring the mitochondrial damages and by densitometry of the mitochondria as a marker of the density of the granules of the mitochondrial matrix. For demonstrating the cytochrome oxidase activity, 3,3'-diaminobenzidine (DAB) reaction was used. Histochemical modifications of the cytochrome oxidase activities were evaluated by using a scoring system of localization of the cytochrome oxidase and by densitometry of the mitochondria. In the ischemic groups, ultrastructural changes, such as a decrease of mitochondrial matrix granules and disruption of cristae, were observed from 60 min. ischemia. However, no particular ultrastructural changes were observed from 60 min. to 240 min. ischemia. In reperfusion, after 60 min. ischemia, the ultrastructures were recovered, but they were not recovered in reperfusion after 120 min. ischemia. The cytochrome oxidase activities did not change until 120 min. ischemia. However, in 240 min. ischemic groups the cytochrome oxidase was sparsely localized. Histochemical changes of cytochrome oxidase activities may lag behind the ultrastructural changes of mitochondria.
Cell Mol Biol (Noisy-le-grand) 1994 Dec
PMID:Ultrastructural and histochemical changes of mitochondria in global ischemic cardiac muscle of rat. 787 87

Previous studies demonstrated that one of the most significant cellular responses of the rabbit urinary bladder to partial outlet obstruction is a 50% decrease in the activities of the mitochondrial enzymes citrate synthase and malate dehydrogenase, when calculated as either activity per unit mass or activity per mg protein. A major question arose from these studies: Are the mitochondrial enzyme activities per mitochondrion reduced, or is the number of mitochondria per unit tissue mass reduced? The current experiments were designed to study the sequential changes in the activities of mitochondrial oxidative enzymes following partial outlet obstruction. The activities of NADH-cytochrome c reductase (NCCR), cytochrome oxidase (CO), citrate synthase (CS) and malate dehydrogenase (MDH) were measured in whole tissue homogenates and in mitochondrial preparations of separated bladder mucosa and muscle, from normal bladders, and, from hypertrophied bladders at 1, 3, and 7 days following partial outlet obstruction. The results can be summarized as follows: 1) Whole tissue homogenates: Activities of all enzymes were reduced to approximately 50% of control at 1 day following partial outlet obstruction. NCCR and CO activities returned to 75 and 85% of control respectively by 7 days post-obstruction; CS activity did not show any significant recovery over the 7 day period. 2) Mucosal and smooth muscle mitochondrial preparations: Activities of all enzymes were decreased significantly by 50% or greater at 1 day following partial outlet obstruction. The cytochrome (NCCR and CO) enzyme activities returned to control levels by 7 days post-obstruction; CS activity showed only a minor recovery over this time period. These results show that mitochondrial enzyme activity is significantly impaired immediately following partial outlet outlet obstruction, and whereas the activity of the cytochrome enzymes NCCR and CO recover to control levels (in the mitochondrial preparations) within 7 days post obstruction, the Krebs cycle enzymes (CS and MD) show no significant recovery. Thus, the regulatory mechanisms for the cytochromes is significantly different from that for the enzymes of the krebs cycle.
Mol Cell Biochem 1994 Dec 07
PMID:Alterations of mitochondrial oxidative metabolism in rabbit urinary bladder after partial outlet obstruction. 787 5

In the rabbit, partial outlet obstruction of the urinary bladder results in significant changes in the physiology, cellular structure, and cellular metabolism of that organ. One of the most striking changes observed is a 50% decrease in oxidative metabolism. Here we investigate whether the function of the mitochondrial (mt) genetic system is altered in rabbit bladder tissue following partial outlet obstruction. Southern analyses of total DNA prepared from bladder tissue excised as a function of time after initiation of partial outlet obstruction showed that the relative number of copies of the mt genome decreases as much as 10-fold during the first 7 d after obstruction, and that this attenuated mt genome copy number is maintained until at least 14 d post-obstruction. Northern analyses, in contrast, showed that mt COII and cytochrome b transcript levels initially decrease but recover to control levels by about 5 d after obstruction; that level is maintained through 14 d post-obstruction. Enzymatic analysis of cytochrome oxidase and NADH cytochrome c reductase activities in obstructed bladder tissue gave results which paralleled the pattern in the mt RNA analyses. Surprisingly, transcript levels for the mt-related nuclear COIV gene rapidly decreased to about 50% of control levels following obstruction and remained there until 14 d post-obstruction. These results indicate that partial outlet obstruction of the rabbit bladder leads to significant changes in the status and expression of the mt genetic system in bladder tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1994 Dec 07
PMID:Partial outlet obstruction of the rabbit bladder results in changes in the mitochondrial genetic system. 787 8

The genes for a new type of a haem-copper cytochrome oxidase were cloned from Rhodobacter capsulatus strain 37b4, using the Bradyrhizobium japonicum fixNOQP gene region as a hybridizing probe. Four genes, probably organized in an operon (ccoNOQP), were identified; their products share extensive amino acid sequence similarity with the FixN, O, Q and P proteins that have recently been shown to be the subunits of a cb-type oxidase. CcoN is a b-type cytochrome, CcoO and CcoP are membrane-bound mono- and dihaem c-type cytochromes and CcoQ is a small membrane protein of unknown function. Genes for a similar oxidase are also present in other non-rhizobial bacterial species such as Azotobacter vinelandii, Agrobacterium tumefaciens and Pseudomonas aeruginosa, as revealed by polymerase chain reaction analysis. A ccoN mutant was constructed whose phenotype, in combination with the structural information on the gene products, provides evidence that the CcoNOQP oxidase is a cytochrome c oxidase of the cb type, which supports aerobic respiration in R. capsulatus and which is probably identical to the cbb3-type oxidase that was recently purified from a different strain of the same species. Mutant analysis also showed that this oxidase has no influence on photosynthetic growth and nitrogen-fixation activity.
Mol Microbiol 1994 Nov
PMID:The ccoNOQP gene cluster codes for a cb-type cytochrome oxidase that functions in aerobic respiration of Rhodobacter capsulatus. 789 58

Two-dimensional crystals of beef heart mitochondrial cytochrome c oxidase dimers were labeled at Cys-115 of subunit III with a monomaleimide derivative of an undecagold cluster compound. The binding site of the gold cluster compound and hence the site of subunit III were identified by image processing of cryoelectron micrographs of the crystals preserved in a mixture of glucose and uranyl acetate. The shape of the cytochrome oxidase dimer can be approximated as a parallelogram which is 44 by 82 A with an included angle of 80 degrees oriented with its long dimension along the a axis of the crystal. Labeling of subunit III was confirmed by a shift in the mobility of approximately 50% of subunit III molecules upon electrophoresis in polyacrylamide gels in the presence of sodium dodecyl sulfate. Averaged images of undecagold cluster labeled crystals and of unlabeled crystals were calculated; each image represents an average of approximately 17,000 molecules of either labeled or unlabeled cytochrome oxidase. On the basis of a statistical analysis of the differences between the two images, the gold cluster binds along a line 30 degrees from the a axis and 29 A from the center of the dimer. This result is interpreted in the context of other structural studies including the site of cytochrome c binding which Frey and Murray found to be near the a axis and 18 A from the center of the dimer [Frey, T. G., & Murray, J. M. (1994) J. Mol. Biol. 237, 275-297].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electron microscopy of cytochrome c oxidase crystals: labeling of subunit III with a monomaleimide undecagold cluster compound. 794 82

Brains from 5 patients with Alzheimer's disease (AD) showed a 50%-65% decrease in mRNA levels of the mitochondrial-encoded cytochrome oxidase (COX, a marker of oxidative metabolism) subunits I and III in the middle temporal association neocortex, but not in the primary motor cortex, as compared to 5 control brains. The amount of mitochondrial-encoded 12S rRNA was not altered, nor was the amount of nuclear-encoded lactate dehydrogenase B mRNA (a marker of glycolytic metabolism). These data suggest that the decrease in COX I and III subunits mRNA in affected brain regions may contribute to reduced brain oxidative metabolism in AD.
Brain Res Mol Brain Res 1994 Jul
PMID:Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. 796 73

The bodonids and cryptobiids represent an early diverged sister group to the trypanosomatids among the kinetoplastid protozoa. The trypanosome type of uridine insertion-deletion RNA editing was found to occur in the cryptobiid fish parasite Trypanoplasma borreli. A pan-edited ribosomal protein, S12, and a novel 3'- and 5'-edited cytochrome b, in addition to an unedited cytochrome oxidase III gene and an apparently unedited 12S rRNA gene, were found in a 6-kb fragment of the 80- to 90-kb mitochondrial genome. The gene order differs from that in trypanosomatids, as does the organization of putative guide RNA genes; guide RNA-like molecules are transcribed from tandemly repeated 1-kb sequences organized in 200- and 170-kb molecules instead of minicircles. The presence of pan-editing in this lineage is consistent with an ancient evolutionary origin of this process.
Mol Cell Biol 1994 Dec
PMID:RNA editing and mitochondrial genomic organization in the cryptobiid kinetoplastid protozoan Trypanoplasma borreli. 796 54


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