Mammalian mitochondrial mutants selected for resistance to the cytochromeb inhibitors HQNO or myxothiazol

Howell, Neil; Bantel, Astrid de; Huang, Ping

doi:10.1007/bf01539476

Cited by 18 publications

(8 citation statements)

References 34 publications

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“…These could be naturally occurring variants from different strains or species of mice and rodents or additional mutants resistant to mitochondrial OXPHOS inhibitors such as rotenone, antimycin A, and mycidin (13,(37)(38)(39)(40)(41). In addition, the recovery of somatic mtDNA mutants that accumulate during normal aging by clonal expansion of brain mtDNAs in synaptosome cybrids (19) also may permit the introduction of naturally occurring deleterious somatic mtDNA mutations into mice.…”

Section: Discussionmentioning

confidence: 99%

Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice

Sligh

Levy

Waymire

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

123

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We report a method for introducing mtDNA mutations into the mouse female germ line by means of embryonic stem (ES) cell cybrids. Mitochondria were recovered from the brain of a NZB mouse by fusion of synaptosomes to a mtDNA-deficient (°) cell line. These cybrids were enucleated and the cytoplasts were electrofused to rhodamine-6G (R-6G)-treated female ES cells. The resulting ES cell cybrids permitted transmission of the NZB mtDNAs through the mouse maternal lineage for three generations. Similarly, mtDNAs from a partially respiratory-deficient chloramphenicol-resistant (CAP R ) cell line also were introduced into female chimeric mice and were transmitted to the progeny. CAP R chimeric mice developed a variety of ocular abnormalities, including congenital cataracts, decreased retinal function, and hamaratomas of the optic nerve. The germ-line transmission of the CAP R mutation resulted in animals with growth retardation, myopathy, dilated cardiomyopathy, and perinatal or in utero lethality. Skeletal and heart muscle mitochondria of the CAP R mice were enlarged and atypical with inclusions. This mouse ES cell-cybrid approach now provides the means to generate a wide variety of mouse models of mitochondrial disease.

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Section: Discussionmentioning

confidence: 99%

Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice

Sligh

Levy

Waymire

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

123

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“…To date, mutants resistant to different classes of inhibitors have been isolated in both the budding (Subik, 1975) and the fission (Lang et al, 1975) yeast, and in mouse (Howell et al, 1983) mitochondria. We have also reported the isolation of similar mutants from the photosynthetic bacterium R. capsulatus (Daldal et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Mutations conferring resistance to quinol oxidation (Qz) inhibitors of the cyt bc1 complex of Rhodobacter capsulatus.

et al. 1989

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Several spontaneous mutants of the photosynthetic bacterium Rhodobacter capsulatus resistant to myxothiazol, stigmatellin and mucidin‐‐inhibitors of the ubiquinol: cytochrome c oxidoreductase (cyt bc1 complex)‐‐were isolated. They were grouped into eight different classes based on their genetic location, growth properties and inhibitor cross‐resistance. The petABC (fbcFBC) cluster that encodes the structural genes for the Rieske FeS protein, cyt b and cyt c1 subunits of the cyt bc1 complex was cloned out of the representative isolates and the molecular basis of inhibitor‐resistance was determined by DNA sequencing. These data indicated that while one group of mutations was located outside the petABC(fbcFBC) cluster, the remainder were single base pair changes in codons corresponding to phylogenetically conserved amino acid residues of cyt b. Of these substitutions, F144S conferred resistance to myxothiazol, T163A and V333A to stigmatellin, L106P and G152S to myxothiazol + mucidin and M140I and F144L to myxothiazol + stigmatellin. In addition, a mutation (aer126) which specifically impairs the quinol oxidase (Qz) activity of the cyt bc1 complex of a non‐photosynthetic mutant (R126) was identified to be a glycine to an aspartic acid replacement at position 158 of cyt b. Six of these mutations were found between amino acid residues 140 and 163, in a region linking the putative third and fourth transmembrane helices of cyt b. The non‐random clustering of several inhibitor‐resistance mutations around the non‐functional aer126 mutation suggests that this region may be involved in the formation of the Qz inhibitor binding/quinol oxidation domain(s) of the cyt bc1 complex. Of the two remaining mutations, the V333A replacement conferred resistance to stigmatellin exclusively and was located in another region toward the C terminus of cyt b. The L106P substitution, on the other hand, was situated in the transmembrane helix II that carries two conserved histidine residues (positions 97 and 111 in R. capsulatus) considered to be the axial ligands for the heme groups of cyt b. The structural and functional roles of the amino acid residues involved in the acquisition of Qz inhibitor resistance are discussed in terms of the primary structure of cyt b and in relation to the natural inhibitor‐resistance of various phylogenetically related cyt bc/bf complexes.

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“…Antimycin and ascorbic acid were obtained from Sigma. Mucidin was obtained from Dr. N. Howell, who has used the inhibitor to select resistant mutants (Howell et al, 1983) and who received the compound from Dr. V. Musilek (Prague). Strobilurin A was provided by Dr. T. Anke (Kaiserslautern).…”

Section: Methodsmentioning

confidence: 99%

“…The importance of such antibiotics is increased by the recent application of genetic methods to further delineate their sites of action. Numerous mutants of yeast and mouse cells resistant to antimycin and myxothiazol have been isolated, and these mutations have been mapped to the mitochondrial cytochrome 6 gene (Roberts et al, 1980;Thierbach & Michaelis, 1982;Howell et al, 1983). As the genetic approaches are extended to locate the mutant loci within the sequence of the cytochrome 6 gene (Nobrega & Tzagaloff, 1980;Anderson et al, 1982) and these results are interpreted together with biochemical information on these inhibitors, it should be possible to locate the center i and center o domains on cytochrome 6 and to relate these to the location of the hemes of 6-562 and 6-566.…”

mentioning

confidence: 99%

Mucidin and strobilurin A are identical and inhibit electron transfer in the cytochrome bc1 complex of the mitochondrial respiratory chain at the same site as myxothiazol

Jagow¹,

Gribble²,

Trumpower³

1986

Biochemistry

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Mucidin and strobilurin A, antifungal antibiotics isolated from the basidiomycetes Oudemansiella mucida and Strobiluris tenacellus, respectively, inhibit electron-transfer reactions in the cytochrome bc1 complex of the mitochondrial respiratory chain. The two compounds have identical effects on oxidation-reduction reactions of the cytochromes b and c1 in isolated succinate-cytochrome c reductase. They inhibit reduction of cytochrome c1 by succinate but do not inhibit reduction of cytochrome b. When added in combination with antimycin, either inhibitor blocks reduction of both cytochromes b and c1. Mucidin and strobilurin A differ from antimycin in that they inhibit, rather than promote, oxidant-induced reduction of cytochrome b. They also differ from antimycin in that they do not block reduction of cytochrome b by succinate when cytochrome c1 is previously reduced by ascorbate and they do not inhibit oxidation of cytochrome b by fumarate. These effects of mucidin and strobilurin A are, however, qualitatively identical with those of myxothiazol, an antibiotic that inhibits respiration by binding to cytochrome b [Von Jagow, G., Ljungdahl, P. O., Graf, P., Ohnishi, T., & Trumpower, B. L. (1984) J. Biol. Chem. 259, 6319-6326]. Mucidin and strobilurin A have identical UV and mass spectra, and they elute together on high-pressure liquid chromatography. We thus conclude that these antibiotics, although isolated from different bacteria, are structurally identical. Our results indicate that strobilurin A and mucidin inhibit electron transport at the same site as myxothiazol and not at the antimycin site, as previously reported [Subik, J., Behren, M., & Musilek, V. (1974) Biochem. Biophys. Res. Commun. 57, 17-22].

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Mammalian mitochondrial mutants selected for resistance to the cytochromeb inhibitors HQNO or myxothiazol

Cited by 18 publications

References 34 publications

Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice

Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice

Mutations conferring resistance to quinol oxidation (Qz) inhibitors of the cyt bc1 complex of Rhodobacter capsulatus.

Mucidin and strobilurin A are identical and inhibit electron transfer in the cytochrome bc1 complex of the mitochondrial respiratory chain at the same site as myxothiazol

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