scholarly journals Molecular mechanism and physiological role of active–deactive transition of mitochondrial complex I

2013 ◽  
Vol 41 (5) ◽  
pp. 1325-1330 ◽  
Author(s):  
Marion Babot ◽  
Alexander Galkin
Keyword(s):  
Complex I ◽  
Physiological Role ◽  
Protective Mechanism ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
The Status ◽  
Nitric Oxide Metabolites

The unique feature of mitochondrial complex I is the so-called A/D transition (active–deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min−1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1–10 min−1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

scholarly journals Intrastriatal Neurotoxin Injections Reduce in Vitro and in Vivo Binding of Radiolabeled Rotenoids to Mitochondrial Complex I

1997 ◽  
Vol 17 (3) ◽  
pp. 265-272 ◽  
Author(s):  
Michael R. Kilbourn ◽  
Avgui Charalambous ◽  
Kirk A. Frey ◽  
Phillip Sherman ◽  
Donald S. Higgins ◽  
...  
Keyword(s):  
Quinolinic Acid ◽  
Complex I ◽  
Rat Striatum ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
In Vivo Binding ◽  
Vitro Binding ◽  
Direct Competition

The in vivo and in vitro bindings of radiolabeled rotenoids to mitochondrial complex I of rat striatum were examined after unilateral intrastriatal injections of quinolinic acid or 1-methyl-4-phenylpyridinium salt (MPP+). Quinolinic acid produced significant, similar losses of in vivo binding of [11C]dihydrorotenol ([11C]DHROL: 40%) and in vitro binding of [3H]dihydrorotenone ([3H]DHR: 53%) in the injected striata at 13 days after the injection of neurotoxin. MPP+ reduced in vivo binding of [11C]DHROL (up to −55%) as measured 1.5 to 6 h after its administration. Reductions of in vivo [11C]DHROL binding after either quinolinic acid or MPP+ injections did not correlate with changes in striatal blood flow as measured with [14C]iodoantipyrine. These results are consistent with losses of complex I binding sites for radiolabeled rotenoids, produced using cell death (quinolinic acid) or direct competition for the binding site (MPP+). Appropriately radiolabeled rotenoids may be useful for in vivo imaging studies of changes of complex I in neurodegenerative diseases.

scholarly journals Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tatsuhiro Terada ◽  
Joseph Therriault ◽  
Min Su Peter Kang ◽  
Melissa Savard ◽  
Tharick Ali Pascoal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Clinical Symptoms ◽  
Mitochondrial Complex I ◽  
Braak Stage ◽  
Mitochondrial Complex ◽  
Temporal Area

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

scholarly journals Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin

1997 ◽  
Vol 185 (3) ◽  
pp. 579-582 ◽  
Author(s):  
Davide Ferrari ◽  
Paola Chiozzi ◽  
Simonetta Falzoni ◽  
Stefania Hanau ◽  
Francesco Di  Virgilio
Keyword(s):  
Plasma Membrane ◽  
P2x7 Receptor ◽  
Purinergic Receptor ◽  
Present Report ◽  
Physiological Role ◽  
Bacterial Endotoxin ◽  
Microglial Cells

Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.

Immunomodulation by 17β-estradiol in bivalve hemocytes

2006 ◽  
Vol 291 (3) ◽  
pp. R664-R673 ◽  
Author(s):  
Laura Canesi ◽  
Caterina Ciacci ◽  
Lucia Cecilia Lorusso ◽  
Michele Betti ◽  
Tiziana Guarnieri ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Hydrolytic Enzymes ◽  
Physiological Role ◽  
Estrogen Receptor Α ◽  
Nitrite Accumulation ◽  
No Production ◽  
17Β Estradiol

In mammals, estrogens have dose- and cell-type-specific effects on immune cells and may act as pro- and anti-inflammatory stimuli, depending on the setting. In the bivalve mollusc Mytilus, the natural estrogen 17β-estradiol (E2) has been shown to affect neuroimmune functions. We have investigated the immunomodulatory role of E2 in Mytilus hemocytes, the cells responsible for the innate immune response. E2 at 5–25 nM rapidly stimulated phagocytosis and oxyradical production in vitro; higher concentrations of E2 inhibited phagocytosis. E2-induced oxidative burst was prevented by the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine and superoxide dismutase, indicating involvement of NO and O2−; NO production was confirmed by nitrite accumulation. The effects of E2 were prevented by the antiestrogen tamoxifen and by specific kinase inhibitors, indicating a receptor-mediated mechanism and involvement of p38 MAPK and PKC. E2 induced rapid and transient increases in the phosphorylation state of PKC, as well as of a aCREB-like (cAMP responsive element binding protein) transcription factor, as indicated by Western blot analysis with specific anti-phospho-antibodies. Localization of estrogen receptor-α- and -β-like proteins in hemocytes was investigated by immunofluorescence confocal microscopy. The effects of E2 on immune function were also investigated in vivo at 6 and 24 h in hemocytes of E2-injected mussels. E2 significantly affected hemocyte lysosomal membrane stability, phagocytosis, and extracellular release of hydrolytic enzymes: lower concentrations of E2 resulted in immunostimulation, and higher concentrations were inhibitory. Our data indicate that the physiological role of E2 in immunomodulation is conserved from invertebrates to mammals.

Abstract 404: High-throughput Screening Reveals the Mitochondrial Complex I Inhibitor Nornicotine is Cardioprotective in Ischemia-reperfusion Injury When Delivered at Reperfusion

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jimmy Zhang ◽  
Marcin K Karcz ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Functional Recovery ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Early Reperfusion ◽  
Perfused Hearts

Background: To date, there are no FDA-approved therapies for the reduction of infarct size in acute myocardial infarction. Previously, we developed a cell-based phenotypic assay of ischemia-reperfusion (IR) injury, which was used to identify novel cytoprotective agents delivered prior to ischemia. Herein, we sought to identify cytoprotective agents in a more clinically relevant model: drug delivery at reperfusion, and to investigate possible underlying mechanisms of protection. Methods: Primary adult mouse cardiomyocytes were subjected to simulated IR injury using a modified Seahorse XF24 apparatus with drug addition at the onset of reperfusion. Cell death was estimated using LDH release. Drugs which protected cardiomyocytes in vitro were tested in a Langendorff model of IR injury, measuring functional recovery and infarct size. In separate experiments, metabolites extracted from perfused hearts were resolved by HPLC. Results: Nornicotine was identified as a cardioprotective agent in the screen. In perfused hearts, 10 nM nornicotine injected at the onset of reperfusion improved functional recovery and decreased in infarct size (13.1% ± 2.4 vs 49.2% ± 2.5 in non-treated hearts, p<0.05, n=16-20). Nornicotine also exhibited profound inhibitory effects on mitochondrial complex I activity. Succinate is known to accumulate in ischemia, and its rapid consumption during early reperfusion exacerbates reperfusion injury via ROS generation from electron backflow through complex I [PMID: 25383517]. In non-treated hearts, we confirmed that high post ischemic levels of succinate rapidly declined during the first 2 min of reperfusion. In contrast, nornicotine slowed post-ischemic succinate consumption, suggesting that electron backflow through complex I is the major pathway driving succinate consumption. Conclusions: Herein, we demonstrated that nornicotine was cardioprotective when delivered at early reperfusion in vitro and ex vivo. The mechanism of cardioprotection may be due to inhibition of rapid succinate consumption during early reperfusion via reverse electron flow back through complex I.

scholarly journals Two Quenchers Formed During Photodamage of Phostosystem II and The Role of One Quencher in Preemptive Photoprotection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alonso Zavafer ◽  
Ievgeniia Iermak ◽  
Mun Hon Cheah ◽  
Wah Soon Chow
Keyword(s):  
Chlorophyll Fluorescence ◽  
Photosystem Ii ◽  
Time Course ◽  
Physiological Role ◽  
Reaction Centre ◽  
Time Resolved ◽  
Fluorescence Quencher

AbstractThe quenching of chlorophyll fluorescence caused by photodamage of Photosystem II (qI) is a well recognized phenomenon, where the nature and physiological role of which are still debatable. Paradoxically, photodamage to the reaction centre of Photosystem II is supposed to be alleviated by excitation quenching mechanisms which manifest as fluorescence quenchers. Here we investigated the time course of PSII photodamage in vivo and in vitro and that of picosecond time-resolved chlorophyll fluorescence (quencher formation). Two long-lived fluorescence quenching processes during photodamage were observed and were formed at different speeds. The slow-developing quenching process exhibited a time course similar to that of the accumulation of photodamaged PSII, while the fast-developing process took place faster than the light-induced PSII damage. We attribute the slow process to the accumulation of photodamaged PSII and the fast process to an independent quenching mechanism that precedes PSII photodamage and that alleviates the inactivation of the PSII reaction centre.

Heterocyclic Analogues of Squamocin as Inhibitors of Mitochondrial Complex I. On the Role of the Terminal Lactone of Annonaceous Acetogenins

Biochemistry ◽  
2006 ◽  
Vol 45 (8) ◽  
pp. 2721-2728 ◽  
Author(s):  
Romain A. Duval ◽  
Guy Lewin ◽  
Eva Peris ◽  
Nadia Chahboune ◽  
Aurelio Garofano ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Annonaceous Acetogenins

scholarly journals Vitamin D and prostate cancer

2013 ◽  
Vol 66 (5-6) ◽  
pp. 259-262
Author(s):  
Goran Marusic ◽  
Dimitrije Jeremic ◽  
Sasa Vojinov ◽  
Natasa Filipovic ◽  
Milan Popov
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Physiological Role ◽  
In Vivo Studies ◽  
Vitamin D Metabolism ◽  
Genetic Changes ◽  
Metabolic Role

In addition to the metabolic role of vitamin D, which is well known and clearly defined, there have been many hypotheses regarding its anti-proliferative and pro-apoptotic role. Epidemiology and Significance of Prostate Cancer. Prostate cancer is the second most common malignancy in men. Long period of cancerogenesis, available tumor markers and high incidence make this cancer ideal for preventive measures. Physiological Role of Vitamin D and its Effect on Prostate Cancer Cells. In vitro and in vivo studies have shown the anti-proliferative and pro-apoptopic role of vitamin D. Disorders of vitamin D metabolism are noted in vitamin D gene level, vitamin D receptor, vitamin D responsive elements and androgen receptors. We present the most important effect of those changes on vitamin D metabolism. Conclusion. Available studies on vitamin D level in serum, prostate tissue, observed activity of vitamin D enzymes and genetic changes give us only a slight insight into the basic mechanisms of vitamin D action in the development of prostate cancer; therefore, further investigations are needed.

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