scholarly journals Inhibition of Mitochondrial Complex III in Candida Albicans ADH1 Deletion Mutant Attenuates Its Pathogenicity Significantly

2021 ◽  
Author(s):  
Hui Guo ◽  
Yi Shan Zhang ◽  
Yan Jun Song ◽  
Ya Jing Zhao ◽  
Shui Xiu Li ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Alternative Oxidase ◽  
Oxidase Inhibitor ◽  
Complex Iii ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Aerobic Growth ◽  
Transport Chain ◽  
Atp Generation

Abstract Fermentation and aerobic respiration in mitochondria are coordinately regulated and compensated either when C. albicans grows in vitro or in the hosts, and the creature gain the strong viability. It’s insufficient to influent the growth, reproduction and pathogenicity of C. albicans by inhibiting the electron transport chain (ECT) CI, CII, CIII, CV, or fermentation related gene ADH1. Our study showed that the induction of AA (inhibitor of complex III) rather than SHAM (alternative oxidase inhibitor) abolishes the mitochondrial function completely （96% less ATP generation, 59% reduction in MMP), and increases ROS production significantly in ADH1-deleted mutant ( adh1Δ/ adh1Δ ) that in turn becomes hypersensitive to azole and apoptosis, less viable and more difficult to form hyphae. At the same time, the expression of virulence related genes ALS3 and HWP1 were significantly lower than that of WT under AA induction. Under the induction of AA, the mitochondrial function of WT was slightly damaged and cell apoptosis increased slightly，ROS production and sensitivity of azoles increased significantly, but mycelium formation and the growth of cells were not affected. Under aerobic growth, we observed an ADH1 - dependent mitochondrial effect in C. albicans demonstrated by 64% less ATP generation, 58% reduction in MMP and significant elevations of the ROS and apoptosis in ADH1 -deleted mutant. However, mycelium formation and azole susceptibility are not affected. Our results suggested that ADH1 plus CIII played an important role in antifungal activity by damaging mitochondrial function, inhibiting cell growth and hyphae formation, promoting apoptosis and reducing pathogenicity.

scholarly journals Redox Regulation of Calcium Signaling in Cancer Cells by Ascorbic Acid Involving the Mitochondrial Electron Transport Chain

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Grigory G. Martinovich ◽  
Elena N. Golubeva ◽  
Irina V. Martinovich ◽  
Sergey N. Cherenkevich
Keyword(s):  
Ascorbic Acid ◽  
Electron Transport ◽  
Calcium Signaling ◽  
Electron Transport Chain ◽  
Redox Regulation ◽  
Complex Iii ◽  
Antimycin A ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Transport Chain

Previously, we have reported that ascorbic acid regulates calcium signaling in human larynx carcinoma HEp-2 cells. To evaluate the precise mechanism of Ca2+ release by ascorbic acid, the effects of specific inhibitors of the electron transport chain components on mitochondrial reactive oxygen species (ROS) production and Ca2+ mobilization in HEp-2 cells were investigated. It was revealed that the mitochondrial complex III inhibitor (antimycin A) amplifies ascorbate-induced Ca2+ release from intracellular stores. The mitochondrial complex I inhibitor (rotenone) decreases Ca2+ release from intracellular stores in HEp-2 cells caused by ascorbic acid and antimycin A. In the presence of rotenone, antimycin A stimulates ROS production by mitochondria. Ascorbate-induced Ca2+ release in HEp-2 cells is shown to be unaffected by catalase. The results obtained suggest that Ca2+ release in HEp-2 cells caused by ascorbic acid is associated with induced mitochondrial ROS production. The data obtained are in line with the concept of redox signaling that explains oxidant action by compartmentalization of ROS production and oxidant targets.

scholarly journals Impaired Mitochondrial Function Results from Oxidative Stress in the Full-Term Placenta of Sows with Excessive Back-Fat

Animals ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 360 ◽  
Author(s):  
Liang Tian ◽  
Jiahe Huang ◽  
Aiyou Wen ◽  
Peishi Yan
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Placental Tissue ◽  
Term Placenta ◽  
Mitochondrial Alterations ◽  
Transport Chain ◽  
Elevated Protein ◽  
Atp Generation ◽  
Complex I Activity

The aim of this study was to determine the effect of excessive back-fat (BF) of sows on placental oxidative stress, ATP generation, mitochondrial alterations in content and structure, and mitochondrial function in isolated trophoblasts. Placental tissue was collected by vaginal delivery from BFI (15–20 mm, n = 10) and BFII (21–27 mm, n = 10) sows formed according to BF at mating. Our results demonstrated that excessive back-fat contributed to augmented oxidative stress in term placenta, as evidenced by excessive production of ROS, elevated protein carbonylation, and reduced SOD, GSH-PX, and CAT activities (p < 0.05). Indicative of mitochondrial dysfunction, reduced mitochondrial respiration in cultured trophoblasts was linked to decreased ATP generation, lower mitochondrial Complex I activity and reduced expression of electron transport chain subunits in placenta of BFII sows (p < 0.05). Meanwhile, we observed negative alterations in mitochondrial biogenesis and structure in the placenta from BFII group (p < 0.05). Finally, our in vitro studies showed lipid-induced ROS production resulted in mitochondrial alterations in trophoblasts, and these effects were blocked by antioxidant treatment. Together, these data reveal that excessive back-fat aggravates mitochondrial injury induced by increased oxidative stress in pig term placenta, which may have detrimental consequences on placental function and therefore impaired fetal growth and development.

Azoxystrobin, a mitochondrial complex III Qo site inhibitor, exerts beneficial metabolic effects in vivo and in vitro

2014 ◽  
Vol 1840 (7) ◽  
pp. 2212-2221 ◽  
Author(s):  
An-Hui Gao ◽  
Yan-Yun Fu ◽  
Kun-Zhi Zhang ◽  
Mei Zhang ◽  
Hao-Wen Jiang ◽  
...  
Keyword(s):  
Complex Iii ◽  
Metabolic Effects ◽  
Mitochondrial Complex ◽  
Qo Site

scholarly journals Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

2020 ◽  
Vol 21 (16) ◽  
pp. 5683
Author(s):  
Joel James ◽  
Mathews Valuparampil Varghese ◽  
Mikhail Vasilyev ◽  
Paul R. Langlais ◽  
Stevan P. Tofovic ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mitochondrial Function ◽  
Cellular Proliferation ◽  
Protein Import ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Complex Iii ◽  
Acid Oxidation ◽  
Mitochondrial Complex ◽  
Mitochondrial Proteome

The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced sustained pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed changes in the rat lung mitochondrial proteome throughout AA treatment. Rats treated with AA for up to 24 days showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p < 0.05). We observed a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and amino acid metabolism, indicating a correlation with diminished mitochondrial function. We also found a significant dysregulation in proteins that controls the protein import machinery and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could potentially lead to the onset of mitochondrial toxicity due to misfolded protein stress. We propose that chronic inhibition of mitochondrial complex III attenuates mitochondrial function by disruption of the global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leads to pulmonary hypertension.

ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction

2014 ◽  
Vol 306 (2) ◽  
pp. F259-F270 ◽  
Author(s):  
Martin Østergaard ◽  
Michael Christensen ◽  
Line Nilsson ◽  
Inge Carlsen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ureteral Obstruction ◽  
Oxidase Inhibitor ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Damage ◽  
Ros Production ◽  
Cox 2 ◽  
And Oxidative Stress

Oxidative stress resulting from unilateral ureteral obstruction (UUO) may be aggravated by increased production of ROS. Previous studies have demonstrated increased cyclooxygenase (COX)-2 expression in renal medullary interstitial cells (RMICs) in response to UUO. We investigated, both in vivo and in vitro, the role of ROS in the induction of COX-2 in rats subjected to UUO and in RMICs exposed to oxidative and mechanical stress. Rats subjected to 3-day UUO were treated with two mechanistically distinct antioxidants, the NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT), to interfere with ROS production. We found that UUO-mediated induction of COX-2 in the inner medulla was attenuated by both antioxidants. In addition, DPI and ROT reduced tubular damage and oxidative stress after UUO. Moreover, mechanical stretch induced COX-2 and oxidative stress in RMICs. Likewise, RMICs exposed to H2O2 as an inducer of oxidative stress showed increased COX-2 expression and activity, both of which were reduced by DPI and ROT. Similarly, ROS production, which was increased after exposure of RMICs to H2O2, was also reduced by DPI and ROT. Furthermore, oxidative stress-induced phosphorylation of ERK1/2 and p38 was blocked by both antioxidants, and inhibition of ERK1/2 and p38 attenuated the induction of COX-2 in RMICs. Notably, COX-2 inhibitors further exacerbated the oxidative stress level in H2O2-exposed RMICs. We conclude that oxidative stress as a consequence of UUO stimulates COX-2 expression through the activation of multiple MAPKs and that the induction of COX-2 may exert a cytoprotective function in RMICs.

scholarly journals Dextromethorphan Reduces Oxidative Stress and Inhibits Uremic Artery Calcification

2021 ◽  
Vol 22 (22) ◽  
pp. 12277
Author(s):  
En-Shao Liu ◽  
Nai-Ching Chen ◽  
Tzu-Ming Jao ◽  
Chien-Liang Chen
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Calcification ◽  
Wistar Rats ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Oxidase Inhibitor ◽  
In Vivo Studies ◽  
Ros Production

Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium–induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium–induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium–induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.

Thrombopoietin (TPO) Regulates HIF-1α Level through Generation of Mitochondrial Reactive Oxygen Species (ROS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3145-3145
Author(s):  
Kozue Yoshida ◽  
Keita Kirito ◽  
Kenneth Kaushansky ◽  
Norio Komatsu
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Mitochondrial Function ◽  
Leukemic Cell ◽  
Complex Iii ◽  
Ros Generation ◽  
Ros Production ◽  
Hematopoietic Stem ◽  
Respiratory Complexes ◽  
Mitochondrial Respiratory

Abstract Hypoxia inducible factor (HIF)-1 is a master transcriptional regulator for adaptation of cells to hypoxia. In addition to hypoxic responses, HIF-1 also plays an important role in the development of hematopoietic stem cells. Genetic deletion of β subunit of HIF-1 causes impairment of hematopoiesis. Culture of hematopoietic stem cells under hypoxic condition induces elevation of HIF-1α , another subunit of HIF-1, and subsequently enhances the growth of these cells. In our previous work we found that thrombopoietin (TPO), an important and non-redundant cytokine required for normal stem cell development, induces HIF-1α elevation in the TPO-dependent human leukemic cell line UT-7/TPO and in Sca-1+/c-kit+/Gr-1- cells (Kirito, K. et.al. Blood 2005). Under normoxic conditions HIF-1α is hydroxylated on proline residues by prolyl hydroxylase (PHD), which leads to its recognition by the von Hippel-Lindau tumor suppressor protein (pVHL), leading to degradation of HIF-1α . Hypoxia inhibits PHD function, blocking ubiquitination of HIF-1α , stabilizing the protein. We found that TPO controls stability of HIF-1α even under normoxic conditions. However, the mechanism by which TPO controls the stability of the protein remains unclear. Recently, several groups have reported that mitochondrial ROS play crucial roles in stabilization of HIF-1α in response to hypoxia. Disruption of mitochondrial function, either by interfering RNA against complex III of the mitochondrial electron transport chain or genetic elimination of cytochrome c, completely abolished the hypoxia-induced HIF-1α response. Based on these findings we hypothesized that ROS might be involved in TPO-induced HIF-1α elevation. To examine our hypothesis, we first tested whether TPO induced ROS production in UT-7/TPO cells using 2′, 7′-dichlorofluorescein diacetate, a redox sensitive fluorescence dye, and found that the hormone clearly induced ROS production in these cells. Next, we analyzed whether TPO-induced ROS generation is required for accumulation of HIF-1α . Pre-treatment of UT-7/TPO cells with the ROS scavenger catalase completely blocked HIF-1α elevation after TPO treatment. Furthermore, diphenylene iodinium (DPI), an inhibitor for ROS generating flavoenzymes including mitochondrial respiratory complexes, also inhibited the effects of TPO on HIF-1α levels. These results indicate that TPO induced HIF-1α activation is mediated by ROS production. To study the molecular pathway(s) by which TPO affects ROS, we tested the effects of ROS blockade on several known TPO-responsive signaling molecules; neither DPI nor catalase affected the activation of JAK2, STAT5, p38-MAPK or p42/p44-ERK induced by TPO, although AKT activation was blocked. Moreover, LY294002, an inhibitor of PI3-kinase and its activation of AKT also blocked of the HIF-1α response to TPO. Finally, inhibition of mitochondrial function in UT-7/TPO cells with rotenone or oligomycin also inhibited TPO-dependent accumulation of HIF-1α without affecting Jak2 activation. In conclusion, we found that TPO regulates HIF-1α levels through activation of ROS generation within mitochondrial respiratory complexes. We speculate that TPO mimics hypoxia by induction of ROS generation at mitochondria and subsequent elevation of HIF-1α , and regulates important genes for metabolisms and survival of hematopoietic stem cells.

scholarly journals Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

2005 ◽  
Vol 1 (6) ◽  
pp. 401-408 ◽  
Author(s):  
Robert D. Guzy ◽  
Beatrice Hoyos ◽  
Emmanuel Robin ◽  
Hong Chen ◽  
Liping Liu ◽  
...  
Keyword(s):  
Oxygen Sensing ◽  
Complex Iii ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Cellular Oxygen

Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria

2008 ◽  
Vol 294 (2) ◽  
pp. C460-C466 ◽  
Author(s):  
Qun Chen ◽  
Shadi Moghaddas ◽  
Charles L. Hoppel ◽  
Edward J. Lesnefsky
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Myocardial Injury ◽  
Complex Iii ◽  
Ischemic Damage ◽  
Ros Production ◽  
Oxygen Species ◽  
Net Production ◽  
Transport Chain

Cardiac ischemia decreases complex III activity, cytochrome c content, and respiration through cytochrome oxidase in subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The reversible blockade of electron transport with amobarbital during ischemia protects mitochondrial respiration and decreases myocardial injury during reperfusion. These findings support that mitochondrial damage occurs during ischemia and contributes to myocardial injury during reperfusion. The current study addressed whether ischemic damage to the electron transport chain (ETC) increased the net production of reactive oxygen species (ROS) from mitochondria. SSM and IFM were isolated from 6-mo-old Fisher 344 rat hearts following 25 min global ischemia or following 40 min of perfusion alone as controls. H2O2release from SSM and IFM was measured using the amplex red assay. With glutamate as a complex I substrate, the net production of H2O2was increased by 178 ± 14% and 179 ± 17% in SSM and IFM ( n = 9), respectively, following ischemia compared with controls ( n = 8). With succinate as substrate in the presence of rotenone, H2O2increased by 272 ± 22% and 171 ± 21% in SSM and IFM, respectively, after ischemia. Inhibitors of electron transport were used to assess maximal ROS production. Inhibition of complex I with rotenone increased H2O2production by 179 ± 24% and 155 ± 14% in SSM and IFM, respectively, following ischemia. Ischemia also increased the antimycin A-stimulated production of H2O2from complex III. Thus ischemic damage to the ETC increased both the capacity and the net production of H2O2from complex I and complex III and sets the stage for an increase in ROS production during reperfusion as a mechanism of cardiac injury.

scholarly journals Important role of PLC-γ1 in hypoxic increase in intracellular calcium in pulmonary arterial smooth muscle cells

2013 ◽  
Vol 304 (3) ◽  
pp. L143-L151 ◽  
Author(s):  
Vishal R. Yadav ◽  
Tengyao Song ◽  
Leroy Joseph ◽  
Lin Mei ◽  
Yun-Min Zheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Muscle Cells ◽  
Complex Iii ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

An increase in intracellular calcium concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) induces hypoxic cellular responses in the lungs; however, the underlying molecular mechanisms remain incompletely understood. We report, for the first time, that acute hypoxia significantly enhances phospholipase C (PLC) activity in mouse resistance pulmonary arteries (PAs), but not in mesenteric arteries. Western blot analysis and immunofluorescence staining reveal the expression of PLC-γ1 protein in PAs and PASMCs, respectively. The activity of PLC-γ1 is also augmented in PASMCs following hypoxia. Lentiviral shRNA-mediated gene knockdown of mitochondrial complex III Rieske iron-sulfur protein (RISP) to inhibit reactive oxygen species (ROS) production prevents hypoxia from increasing PLC-γ1 activity in PASMCs. Myxothiazol, a mitochondrial complex III inhibitor, reduces the hypoxic response as well. The PLC inhibitor U73122, but not its inactive analog U73433, attenuates the hypoxic vasoconstriction in PAs and hypoxic increase in [Ca2+]i in PASMCs. PLC-γ1 knockdown suppresses its protein expression and the hypoxic increase in [Ca2+]i. Hypoxia remarkably increases inositol 1,4,5-trisphosphate (IP3) production, which is blocked by U73122. The IP3 receptor (IP3R) antagonist 2-aminoethoxydiphenyl borate (2-APB) or xestospongin-C inhibits the hypoxic increase in [Ca2+]i. PLC-γ1 knockdown or U73122 reduces H2O2-induced increase in [Ca2+]i in PASMCs and contraction in PAs. 2-APB and xestospongin-C produce similar inhibitory effects. In conclusion, our findings provide novel evidence that hypoxia activates PLC-γ1 by increasing RISP-dependent mitochondrial ROS production in the complex III, which causes IP3 production, IP3R opening, and Ca2+ release, playing an important role in hypoxic Ca2+ and contractile responses in PASMCs.

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