The idebenone metabolite QS10 is an electron donor to complex III and rescues respiration in complex I-deficient cells and rotenone-treated zebrafish

Introduction: Cerebral mitochondrial dysfunction is thought to play a role in the post-cardiac arrest syndrome, propagating secondary morbidity and mortality after return of spontaneous circulation (ROSC). Hypothesis: Based on our previous studies showing a persistent decrease in oxidative phosphorylation (particularly Complex I) and increased mitochondrial fission in a swine model of in-hospital cardiac arrest, we hypothesized that nuclear and mitochondrial genes related to respiratory function would be downregulated and genes promoting mitochondrial fission would be upregulated four hours post-ROSC. Methods: One-month old piglets were subjected to sham anesthesia (n=5) or asphyxial cardiac arrest (n=6; 7 minutes of asphyxia followed by induction of ventricular fibrillation) and treated with 10-20 minutes of AHA guideline-based CPR followed by four hours of standardized post-arrest management and humane euthanasia. RNA was extracted from flash-frozen sections of cerebral cortex using a QIAsymphony robot and sequenced on an Illumina HiSeq. Reads were aligned to the reference (SusScrofa11.1 and NC_012095) using STAR and quantified using subreads. Normalization and differential expression analysis were performed using DESeq2 with RNA quality, intra-arrest and post-ROSC physiologic variables as covariates. All p values were adjusted for multiple comparisons (Benjamini-Hochberg) with a significance cutoff of 0.05. Results: Compared to sham, cardiac arrest animals demonstrated reduced expression of multiple components of the respiratory chain, including NDUFA5 (2.4-fold, p<0.001) and NDUFC1 (2.0-fold, p=0.02), key components of Complex I. Components of Complex III (UQCRB, UQCRH) and Complex IV (COX1, COX7C, COX7A2, COX7B) were also downregulated. Dynamin-2 (DNM2), which increases mitochondrial fission, was upregulated (2.3-fold, p=0.005). There was also differential expression of inner membrane solute channel expression (SLC44A1, SLC25A48 and SLC25A16). Conclusions: Multiple components of the mitochondrial respiratory chain are downregulated 4 hours post-ROSC in the brain, including key components of Complex I with concurrent upregulation of the mitochondrial fission protein dynamin-2.

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Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β-cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1826303 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 10

Author(s):

Lydie Plecitá-Hlavatá ◽

Hana Engstová ◽

Jan Ježek ◽

Blanka Holendová ◽

Jan Tauber ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Islets ◽

Targeted Delivery ◽

Complex I ◽

Chain Complex ◽

Redox Signaling ◽

Complex Iii ◽

Mitochondrial Matrix ◽

Isolated Pancreatic Islets ◽

Superoxide Formation

Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.

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Interleukin-1 (IL-1) Receptor-Associated Kinase-Dependent IL-1-Induced Signaling Complexes Phosphorylate TAK1 and TAB2 at the Plasma Membrane and Activate TAK1 in the Cytosol

Molecular and Cellular Biology ◽

10.1128/mcb.22.20.7158-7167.2002 ◽

2002 ◽

Vol 22 (20) ◽

pp. 7158-7167 ◽

Cited By ~ 207

Author(s):

Zhengfan Jiang ◽

Jun Ninomiya-Tsuji ◽

Youcun Qian ◽

Kunihiro Matsumoto ◽

Xiaoxia Li

Keyword(s):

Plasma Membrane ◽

Complex I ◽

Interleukin 1 ◽

Critical Role ◽

Complex Iii ◽

Receptor Complex ◽

Complex Ii ◽

Jnk Activation ◽

Cytosolic Factors ◽

Sequential Formation

ABSTRACT Interleukin-1 (IL-1) receptor-associated kinase (IRAK) plays an important role in the sequential formation and activation of IL-1-induced signaling complexes. Previous studies showed that IRAK is recruited to the IL-1-receptor complex, where it is hyperphosphorylated. We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1, TAB1, and TAB2, which are preassociated on the membrane before stimulation to form the membrane-associated complex II. The formation of complex II leads to the phosphorylation of TAK1 and TAB2 on the membrane by an unknown kinase, followed by the dissociation of TRAF6-TAK1-TAB1-TAB2 (complex III) from IRAK and consequent translocation of complex III to the cytosol. The formation of complex III and its interaction with additional cytosolic factors lead to the activation of TAK1, resulting in NF-κB and JNK activation. Phosphorylated IRAK remains on the membrane and eventually is ubiquitinated and degraded. Taken together, the new data reveal that IRAK plays a critical role in mediating the association and dissociation of IL-1-induced signaling complexes, functioning as an organizer and transporter in IL-1-dependent signaling.

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Inhibition of the mitochondrial respiratory components (Complex I and Complex III) as stimuli to induce oxidative damage in Oryza sativa L. under thiocyanate exposure

Chemosphere ◽

10.1016/j.chemosphere.2019.125472 ◽

2020 ◽

Vol 243 ◽

pp. 125472 ◽

Cited By ~ 2

Author(s):

Yu-Juan Lin ◽

Xiao-Zhang Yu ◽

Yan-Hong Li ◽

Li Yang

Keyword(s):

Oryza Sativa ◽

Oxidative Damage ◽

Complex I ◽

Oryza Sativa L ◽

Complex Iii ◽

Mitochondrial Respiratory

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Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1320241 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

René G. Feichtinger ◽

Daniel Neureiter ◽

Tom Skaria ◽

Silja Wessler ◽

Timothy L. Cover ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Complex I ◽

Aerobic Glycolysis ◽

Complex Iii ◽

Complex Ii ◽

Gastric Carcinomas ◽

Cellular Energy ◽

Protein Levels ◽

Chemically Induced ◽

Grade 3

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have toHelicobacter pyloriinfection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

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Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms

Acta Parasitologica ◽

10.2478/s11686-014-0203-9 ◽

2014 ◽

Vol 59 (1) ◽

Cited By ~ 7

Author(s):

Subhasish Mondal ◽

Jay Roy ◽

Tanmoy Bera

Keyword(s):

Cell Growth ◽

Cell Survival ◽

Complex I ◽

Leishmania Donovani ◽

Complex Iii ◽

Low Oxygen ◽

Atp Production ◽

Substrate Level Phosphorylation ◽

Metabolic Systems ◽

Substrate Level

AbstractLeishmania, the causative agent of various forms of leishmaniasis, is the significant cause of morbidity and mortality. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. We carried out the study of susceptibilities to different inhibitors of mitochondrial electron transport chain and studies on substrate level phosphorylation in wild-type L. donovani. The amastigote forms of L. donovani are independent on oxidative phosphorylation for ATP production. Indeed, its cell growth was not inhibited by excess oligomycin and dicyclohexylcarbodiimide, which are the most specific inhibitors of the mitochondrial Fo/F1-ATP synthase. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited amastigote cell growth, suggesting the role of complex I and complex III in cell survival. Complex II appeared to have no role in cell survival. To further investigate the site of ATP production, we studied the substrate level phosphorylation, which was involved in the synthesis of ATP. Succinate-pyruvate couple showed the highest substrate level phosphorylation in amastigotes whereas NADH-fumarate and NADH-pyruvate couples failed to produce ATP. In contrast, NADPH-fumarate showed the highest rate of ATP formation in promastigotes. Therefore, we can conclude that substrate level phosphorylation is essential for the survival of amastigote forms of Leishmania donovani.

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Expression of Oxidative Phosphorylation Complexes and Mitochondrial Mass in Pediatric and Adult Inflammatory Bowel Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/9151169 ◽

2022 ◽

Vol 2022 ◽

pp. 1-14

Author(s):

Anna M. Schneider ◽

Mihriban Özsoy ◽

Franz A. Zimmermann ◽

Susanne M. Brunner ◽

René G. Feichtinger ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Oxidative Phosphorylation ◽

Terminal Ileum ◽

Complex I ◽

Older Patients ◽

Pediatric Patients ◽

The Other ◽

Complex Iii ◽

Mitochondrial Mass ◽

Inflammatory Bowel

Introduction. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a multifactorial intestinal disorder but its precise etiology remains elusive. As the cells of the intestinal mucosa have high energy demands, mitochondria may play a role in IBD pathogenesis. The present study is aimed at evaluating the expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes in IBD. Material and Methods. 286 intestinal biopsy samples from the terminal ileum, ascending colon, and rectum from 124 probands (34 CD, 33 UC, and 57 controls) were stained immunohistochemically for all five OXPHOS complexes and the voltage-dependent anion-selective channel 1 protein (VDAC1 or porin). Expression levels were compared in multivariate models including disease stage (CD and UC compared to controls) and age (pediatric/adult). Results. Analysis of the terminal ileum of CD patients revealed a significant reduction of complex II compared to controls, and a trend to lower levels was evident for VDAC1 and the other OXPHOS complexes except complex III. A similar pattern was found in the rectum of UC patients: VDAC1, complex I, complex II, and complex IV were all significantly reduced, and complex III and V showed a trend to lower levels. Reductions were more prominent in older patients compared to pediatric patients and more marked in UC than CD. Conclusion. A reduced mitochondrial mass is present in UC and CD compared to controls. This is potentially a result of alterations of mitochondrial biogenesis or mitophagy. Reductions were more pronounced in older patients compared to pediatric patients, and more prominent in UC than CD. Complex I and II are more severely compromised than the other OXPHOS complexes. This has potential therapeutic implications, since treatments boosting biogenesis or influencing mitophagy could be beneficial for IBD treatment. Additionally, substances specifically stimulating complex I activity should be tested in IBD treatment.

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Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage

Biochemical Journal ◽

10.1042/bj2810709 ◽

1992 ◽

Vol 281 (3) ◽

pp. 709-715 ◽

Cited By ~ 107

Author(s):

K Veitch ◽

A Hombroeckx ◽

D Caucheteux ◽

H Pouleur ◽

L Hue

Keyword(s):

Respiratory Chain ◽

Complex I ◽

Nadh Oxidase ◽

Mitochondrial Respiratory Chain ◽

Complex Iii ◽

Biphasic Response ◽

Ischaemic Damage ◽

Global Ischaemia ◽

Complex I Activity ◽

Mitochondrial Respiratory

Studies of Langendorff-perfused rat hearts have revealed a biphasic response of the mitochondrial respiratory chain to global ischaemia. The initial effect is a 30-40% increase in the rate of glutamate/malate oxidation after 10 min of ischaemia, owing to an increase in the capacity for NADH oxidation. This effect is followed by a progressive decrease in these oxidative activities as the ischaemia is prolonged, apparently owing to damage to Complex I at a site subsequent to the NADH dehydrogenase component. This damage is exacerbated by reperfusion, which causes a further decrease in Complex I activity and also decreases the activities of the other complexes, most notably of Complex III. Perfusion for up to 1 h with anoxic buffer produced only the increase in NADH oxidase activity, and neither anoxia alone, nor anoxia and reperfusion, caused loss of Complex I activity. Perfusing for 3-10 min with anoxic buffer before 1 h of global ischaemia had a significant protective effect against the ischaemia-induced damage to Complex I.

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