Electron‐transfer restoration by vitamin K3 in a complex III‐deficient mutant of S. cerevisiae and sequence of the corresponding cytochrome b mutation

Brivet‐Chevillotte, Paule; Rago, Jean‐Paul di

doi:10.1016/0014-5793(89)81050-6

Cited by 29 publications

(10 citation statements)

References 16 publications

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“…The observed increase in NADH-oxidation by menadione in complex III inhibited fibroblasts is in agreement with the observations of Brivet-Chevillotte and Di Rago (1989), who studied the effects of menadione on NADH-oxidation in a complex IIIdeficient mutant of S. cerevisiae.…”

Section: Resultssupporting

confidence: 91%

Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

Wijburg

Groot

Feller

et al. 1991

J of Inher Metab Disea

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In recent years a large number of patients with different clinical phenotypes due to inborn defects in one or more of the mitochondrial respiratory chain enzyme complexes have been described. Much interesting and exciting work has been done to improve the diagnostic procedures and to elucidate the biochemical and genetic backgrounds of these diseases. However, the results of treatment of patients with a defect in the respiratory chain are often disappointing and difficult to evaluate because of the episodic course of the various diseases.In order to determine the potential value of a new in vitro method for studying the effects of possible therapeutic agents for respiratory chain defects, we studied the effects of menadione (vitamin K 3, 2-methyl-l,4-naphthoquinone) on complex I (NADH:Q1 oxidoreductase) and complex III (CoQ: cytochrome c oxidoreductase) deficient fibroblasts. MATERIALS AND METHODSFibroblasts were cultured from skin biopsies of healthy controls and used after reaching confluency. Lactate and pyruvate production was measured after 4h incubation with 5 mmol/L glucose as previously described (Wijburg et al., 1990). ATP concentration in fibroblasts was measured after 4h incubation at 37°C in KrebsHenseleit bicarbonate buffer with 5mmol/L pyruvate, fortified with 20mmol/L HEPES. The incubation was stopped by the addition of 5 mol/L perchloric acid. After 30min at 4°C the fibroblasts were scraped out of the culture flask using a rubber policeman. The fluid was removed and centrifuged at 4°C to remove denatured protein. 500 #1 of the protein-free acid extract was neutralized to pH 6-7 using 112 #1 of neutralizing buffer (2mol/L KOH, 0.6mol/L MOPS) and centrifuged at 15 000g at 4°C. ATP was measured fluorimetrically in the acid-free extract.For inhibition of complex I, 25 gmol/L of rotenone was added to the incubation medium. Complex III was inhibited by the addition of 18 #mol/L antimycin. Complex IV (cytochrome c oxidase) was inhibited by 5 mmol/L sodium azide in the incubation medium. Menadione (Janssen Chimica, Beerse, Belgium) was added to the incubation medium at a concentration of 5/~mol/L. 293

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Section: Resultssupporting

confidence: 91%

Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

Wijburg

Groot

Feller

et al. 1991

J of Inher Metab Disea

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“…Apparently, only menadione is able to carry out so called cytosolic‐mitochondrial electron shuttling in A. fumigatus . Accordingly, in yeast except of menadione no other quinone was able to bridge the electron transfer of NADH oxidation when complex III was inhibited (Nosoh et al ., ; Brivet‐Chevillotte and di Rago, ). Likewise, menadione restored the electron flow and ATP formation in cardiomyocytes after the inhibition of complex I with rotenone (Shneyvays et al ., ).…”

Section: Discussionmentioning

confidence: 99%

The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

Kroll

Shekhova

Mattern

et al. 2016

Molecular Microbiology

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Aspergillus fumigatus is the predominant airborne pathogenic fungus causing invasive aspergillosis in immunocompromised patients. During infection A. fumigatus has to adapt to oxygen-limiting conditions in inflammatory or necrotic tissue. Previously, we identified a mitochondrial protein to be highly up-regulated during hypoxic adaptation. Here, this protein was found to represent the novel oxidoreductase HorA. In Saccharomyces cerevisiae a homologue was shown to play a role in biosynthesis of coenzyme Q. Consistently, reduced coenzyme Q content in the generated ΔhorA mutant indicated a respective function in A. fumigatus. Since coenzyme Q is involved in cellular respiration and maintaining cellular redox homeostasis, the strain ΔhorA displayed an impaired response to both oxidative and reductive stress, a delay in germination and an accumulation of NADH. Moreover, an increased resistance against antifungal drugs was observed. All phenotypes were completely reversed by the addition of the synthetic electron carrier menadione. The deletion strain ΔhorA showed significantly attenuated virulence in two murine infection models of invasive pulmonary aspergillosis. Therefore, the biosynthesis of coenzyme Q and, particularly, the fungal-specific protein HorA play a crucial role in virulence of A. fumigatus. Due to its absence in mammals, HorA might represent a novel therapeutic target against fungal infections.

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“…One-electron reduction of VK3 leads to the formation of VK3-semiquinone that in the presence of oxygen is oxidized back to VK3 while oxygen is in turn, one-electron reduced to generate Å O À 2 that causes oxidative stress and cytotoxicity. Thus, many of the early biochemical studies showed that VK3 acts as an artificial electron carrier/shunt like ubiquinone (UbQ, CoQ) in the mitochondrial respiratory chain, capable of restoring function when either of complexes I, II or III is inhibited (Slater, 1959;Kolesova et al, 1978;Brivet-Chevillotte and di Rago, 1989;Korneev et al, 1990). VK3 was also used clinically in early attempts to overcome debilitating genetic mutational deficiencies in the respiratory chain complexes of patients suffering from associated mitochondrial disease (reviewed in Mowat et al, 1999;Argov et al, 1986), although bypassing the blockages by administering electron acceptors has not proven very successful.…”

Section: Implications For Cancer Therapy and Why Mitochondria Providementioning

confidence: 99%

The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

Ralph

Rodrı́guez-Enrı́quez

Neužil

et al. 2010

Molecular Aspects of Medicine

308

267

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Electron‐transfer restoration by vitamin K₃ in a complex III‐deficient mutant of S. cerevisiae and sequence of the corresponding cytochrome b mutation

Cited by 29 publications

References 16 publications

Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

Restoration of NADH‐oxidation in complex I and complex III deficient fibroblasts by menadione

The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

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