scholarly journals Divergent features of the coenzyme Q:cytochrome c oxidoreductase complex in Toxoplasma gondii parasites

2020 ◽  
Author(s):  
Jenni A. Hayward ◽  
Esther Rajendran ◽  
Soraya M. Zwahlen ◽  
Pierre Faou ◽  
Giel G. van Dooren
Keyword(s):  
Electron Transport ◽  
Toxoplasma Gondii ◽  
Electron Transport Chain ◽  
Drug Target ◽  
Complex Function ◽  
Protein Composition ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Apicomplexan Parasites ◽  
Transport Chain

AbstractThe mitochondrion is critical for the survival of apicomplexan parasites. Several major anti-parasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase complex (Complex III). Despite being an important drug target, the protein composition of Complex III of apicomplexan parasites has not been elucidated. Here, we undertake a mass spectrometry-based proteomic analysis of Complex III in the apicomplexan Toxoplasma gondii. Along with canonical subunits that are conserved across eukaryotic evolution, we identify several novel or highly divergent Complex III components that are conserved within the apicomplexan lineage. We demonstrate that one such subunit, which we term TgQCR11, is critical for parasite proliferation, mitochondrial oxygen consumption and Complex III activity, and establish that loss of this protein leads to defects in Complex III integrity. We conclude that the protein composition of Complex III in apicomplexans differs from that of the mammalian hosts that these parasites infect.Author summaryApicomplexan parasites cause numerous diseases in humans and animals, including malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). The coenzyme Q:cytochrome c oxidoreductase protein complex (Complex III) performs a central role in the mitochondrial electron transport chain of many eukaryotes. Despite being the target of several major anti-apicomplexan drugs, the protein composition of Complex III in apicomplexans was previously unknown. Our work identifies novel proteins in Complex III of apicomplexans, one of which is critical for complex function and integrity. Our study highlights divergent features of Complex III in apicomplexans, and provides a broader understanding of Complex III evolution in eukaryotes. Our study also provides important insights into what sets this major drug target apart from the equivalent complex in host species.

scholarly journals Divergent features of the coenzyme Q:cytochrome c oxidoreductase complex in Toxoplasma gondii parasites

2021 ◽  
Vol 17 (2) ◽  
pp. e1009211
Author(s):  
Jenni A. Hayward ◽  
Esther Rajendran ◽  
Soraya M. Zwahlen ◽  
Pierre Faou ◽  
Giel G. van Dooren
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Target ◽  
Protein Composition ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Eukaryotic Evolution ◽  
Mitochondrial Oxygen Consumption ◽  
Apicomplexan Parasites ◽  
Transport Chain ◽  
Important Drug

The mitochondrion is critical for the survival of apicomplexan parasites. Several major anti-parasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase complex (Complex III). Despite being an important drug target, the protein composition of Complex III of apicomplexan parasites has not been elucidated. Here, we undertake a mass spectrometry-based proteomic analysis of Complex III in the apicomplexan Toxoplasma gondii. Along with canonical subunits that are conserved across eukaryotic evolution, we identify several novel or highly divergent Complex III components that are conserved within the apicomplexan lineage. We demonstrate that one such subunit, which we term TgQCR11, is critical for parasite proliferation, mitochondrial oxygen consumption and Complex III activity, and establish that loss of this protein leads to defects in Complex III integrity. We conclude that the protein composition of Complex III in apicomplexans differs from that of the mammalian hosts that these parasites infect.

scholarly journals AB0031 T HELPER 17 CELLS WERE SIGNIFICANTLY DECREASED BY MITOCHONDRIAL ELECTRON TRANSPORT CHAIN COMPLEX INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1318.2-1318
Author(s):  
H. R. Lee ◽  
S. J. Yoo ◽  
J. Kim ◽  
I. S. Yoo ◽  
C. K. Park ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Electron Transport ◽  
Disease Activity ◽  
Th17 Cells ◽  
Electron Transport Chain ◽  
Chain Complex ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain ◽  
Healthy Control

Background:Reactive oxygen species (ROS) and T helper 17 (TH17) cells have been known to play an important role in the pathogenesis of rheumatoid arthritis (RA). However, the interrelationship between ROS and TH17 remains unclear in RAObjectives:To explore whether ROS affect TH17 cells in peripheral blood mononuclear cells (PBMC) of RA patients, we analyzed ROS expressions among T cell subsets following treatment with mitochondrial electron transport chain complex inhibitors.Methods:Blood samples were collected from 40 RA patients and 10 healthy adult volunteers. RA activity was divided according to clinical parameter DAS28. PBMC cells were obtained from the whole blood using lymphocyte separation medium density gradient centrifugation. Following PBMC was stained with Live/Dead stain dye, cells were incubated with antibodies for CD3, CD4, CD8, and CD25. After fixation and permeabilization, samples were stained with antibodies for FoxP3 and IL-17A. MitoSox were used for mitochondrial specific staining.Results:The frequency of TH17 cells was increased by 4.83 folds in moderate disease activity group (5.1>DAS28≥3.2) of RA patients compared to healthy control. Moderate RA activity patients also showed higher ratio of TH17/Treg than healthy control (3.57 folds). All RA patients had elevated expression of mitochondrial specific ROS than healthy control. When PBMC cells were treated with 2.5uM of antimycin A (mitochondrial electron transport chain complex III inhibitor) for 16 h, the frequency of TH17 cells was significantly decreased.Conclusion:The mitochondrial electron transport chain complex III inhibitor markedly downregulated the frequency of TH17 cells in moderate disease activity patients with RA. These findings provide a novel approach to regulate TH17 function in RA through mitochondrial metabolism related ROS production.References:[1]Szekanecz, Z., et al., New insights in synovial angiogenesis. Joint Bone Spine, 2010. 77(1): p. 13-9.[2]Prevoo, M.L., et al., Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum, 1995. 38(1): p. 44-8.Disclosure of Interests:None declared

Activity of complex III of the mitochondrial electron transport chain is essential for early heart muscle cell differentiation

2004 ◽  
Vol 18 (11) ◽  
pp. 1300-1302 ◽  
Author(s):  
Dimitry Spitkovsky ◽  
Philipp Sasse ◽  
Eugen Kolossov ◽  
Cornelia Böttinger ◽  
Bernd K. Fleischmann ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Electron Transport ◽  
Muscle Cell ◽  
Heart Muscle ◽  
Electron Transport Chain ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Heart Muscle Cell ◽  
Muscle Cell Differentiation ◽  
Transport Chain

Hypoxia sensing in the fetal chicken femoral artery is mediated by the mitochondrial electron transport chain

2010 ◽  
Vol 298 (4) ◽  
pp. R1026-R1034 ◽  
Author(s):  
Bea Zoer ◽  
Angel L. Cogolludo ◽  
Francisco Perez-Vizcaino ◽  
Jo G. R. De Mey ◽  
Carlos E. Blanco ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Critical Role ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Voltage Gated ◽  
Femoral Arteries ◽  
Transport Chain ◽  
Systemic Arteries

Vascular hypoxia sensing is transduced into vasoconstriction in the pulmonary circulation, whereas systemic arteries dilate. Mitochondrial electron transport chain (mETC), reactive O2 species (ROS), and K+ channels have been implicated in the sensing/signaling mechanisms of hypoxic relaxation in mammalian systemic arteries. We aimed to investigate their putative roles in hypoxia-induced relaxation in fetal chicken (19 days of incubation) femoral arteries mounted in a wire myograph. Acute hypoxia (Po2 ∼2.5 kPa) relaxed the contraction induced by norepinephrine (1 μM). Hypoxia-induced relaxation was abolished or significantly reduced by the mETC inhibitors rotenone (complex I), myxothiazol and antimycin A (complex III), and NaN3 (complex IV). The complex II inhibitor 3-nitroproprionic acid enhanced the hypoxic relaxation. In contrast, the relaxations mediated by acetylcholine, sodium nitroprusside, or forskolin were not affected by the mETC blockers. Hypoxia induced a slight increase in ROS production (as measured by 2,7-dichlorofluorescein-fluorescence), but hypoxia-induced relaxation was not affected by scavenging of superoxide (polyethylene glycol-superoxide dismutase) or H2O2 (polyethylene glycol-catalase) or by NADPH-oxidase inhibition (apocynin). Also, the K+ channel inhibitors tetraethylammonium (nonselective), diphenyl phosphine oxide-1 (voltage-gated K+ channel 1.5), glibenclamide (ATP-sensitive K+ channel), iberiotoxin (large-conductance Ca2+-activated K+ channel), and BaCl2 (inward-rectifying K+ channel), as well as ouabain (Na+-K+-ATPase inhibitor) did not affect hypoxia-induced relaxation. The relaxation was enhanced in the presence of the voltage-gated K+ channel blocker 4-aminopyridine. In conclusion, our experiments suggest that the mETC plays a critical role in O2 sensing in fetal chicken femoral arteries. In contrast, hypoxia-induced relaxation appears not to be mediated by ROS or K+ channels.

scholarly journals Farnesol-Induced Generation of Reactive Oxygen Species via Indirect Inhibition of the Mitochondrial Electron Transport Chain in the Yeast Saccharomyces cerevisiae

1998 ◽  
Vol 180 (17) ◽  
pp. 4460-4465 ◽  
Author(s):  
Kiyotaka Machida ◽  
Toshio Tanaka ◽  
Ken-ichi Fujita ◽  
Makoto Taniguchi
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Reactive Oxygen Species ◽  
Electron Transport ◽  
Growth Inhibition ◽  
Electron Transport Chain ◽  
Complex Iii ◽  
Ros Generation ◽  
Oxygen Species ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain

ABSTRACT The mechanism of farnesol (FOH)-induced growth inhibition ofSaccharomyces cerevisiae was studied in terms of its promotive effect on generation of reactive oxygen species (ROS). The level of ROS generation in FOH-treated cells increased five- to eightfold upon the initial 30-min incubation, while cells treated with other isoprenoid compounds, like geraniol, geranylgeraniol, and squalene, showed no ROS-generating response. The dependence of FOH-induced growth inhibition on such an oxidative stress was confirmed by the protection against such growth inhibition in the presence of an antioxidant such as α-tocopherol, probucol, orN-acetylcysteine. FOH could accelerate ROS generation only in cells of the wild-type grande strain, not in those of the respiration-deficient petite mutant ([rho 0]), which illustrates the role of the mitochondrial electron transport chain as its origin. Among the respiratory chain inhibitors, ROS generation could be effectively eliminated with myxothiazol, which inhibits oxidation of ubiquinol to the ubisemiquinone radical by the Rieske iron-sulfur center of complex III, but not with antimycin A, an inhibitor of electron transport that is functional in further oxidation of the ubisemiquinone radical to ubiquinone in the Q cycle of complex III. Cellular oxygen consumption was inhibited immediately upon extracellular addition of FOH, whereas FOH and its possible metabolites failed to directly inhibit any oxidase activities detected with the isolated mitochondrial preparation. A protein kinase C (PKC)-dependent mechanism was suggested to exist in the inhibition of mitochondrial electron transport since FOH-induced ROS generation could be effectively eliminated with a membrane-permeable diacylglycerol analog which can activate PKC. The present study supports the idea that FOH inhibits the ability of the electron transport chain to accelerate ROS production via interference with a phosphatidylinositol type of signal.

scholarly journals Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qin Yang ◽  
Ling Wang ◽  
Jiaye Liu ◽  
Wanlu Cao ◽  
Qiuwei Pan ◽  
...  
Keyword(s):  
Electron Transport ◽  
Liver Cancer ◽  
Therapeutic Target ◽  
Complex I ◽  
Electron Transport Chain ◽  
Metabolic Reprogramming ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Potential Therapeutic Target ◽  
Transport Chain

AbstractLiver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.

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