Inhibition of electron transport and oxidative phosphorylation in plant mitochondria by gladiolic acid and structurally-related aromatic ortho dialdehydes

1980 ◽  
Vol 58 (1) ◽  
pp. 9-22 ◽  
Author(s):  
G. A. White ◽  
W. B. Elliott
Keyword(s):  
Electron Transport ◽  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Chemical Reactivity ◽  
Plant Mitochondria ◽  
Cross Linking ◽  
Amino Groups ◽  
Intact Mitochondrion

Gladiolic acid (GA, 4-methoxy-5-methyl-o-phthalaldehyde-3-carboxylic acid), an antifungal aromatic ortho dialdehyde produced by Penicillium gladioli was found to be a potent inhibitor of electron transport and oxidative phosphorylation reactions in sweet potato and mung bean mitochondria. Similar results were also found with the naturally occurring ortho dialdehydes, cyclopaldic acid, quadrilineatin, and flavipin as well as the synthetic dialdehydes, 3-formyl opianic acid and o-phthalaldehyde. Because of their highly reactive ortho-diformyl grouping, GA and structurally related dialdehydes apparently act as multisite inhibitors affecting electron transport and oxidative phosphorylation (at each coupling site). Gladiolic acid has no uncoupling effect like 2,4-dinitrophenol and does not have the same point of interaction in the energy transfer process as oligomycin. Several "partial" reactions of phosphorylation (Mg+2–DNP-stimulated ATPase; ATP–Pi exchange) were strongly inhibited by the various dialdehydes. Flavipin and quadrilineatin are potent inhibitors (80% at a concentration of 25 μM) of site III phosphorylation. Gladiolic acid and related ortho dialdehydes inactivate the catalytic activity of native cytochrome c in vitro. Lysyl ε-NH2 rich cytochrome c may be a major site of GA action in the intact mitochondrion. In view of the high chemical reactivity of the ortho-diformyl group, it is suggested that mitochondrial function may be affected by aromatic ortho dialdehydes through a combination of reactions involving cross-linking of amino groups on membrane polypeptides and monofunctional reaction with free amino groups important for enzyme function, including ε-NH2 groups on cytochrome c. Cross-linking in mitochondrial membrane systems might affect function by interfering with molecular motion in the operation of the terminal portion of the electron-transport chain. The primary toxicological mode of action of GA and related dialdehydes appears to be due to inhibition of mitochondrial function.

scholarly journals Stress signalling dynamics of the mitochondrial electron transport chain and oxidative phosphorylation system in higher plants

2019 ◽  
Vol 125 (5) ◽  
pp. 721-736 ◽  
Author(s):  
Corentin Dourmap ◽  
Solène Roque ◽  
Amélie Morin ◽  
Damien Caubrière ◽  
Margaux Kerdiles ◽  
...  
Keyword(s):  
Climate Change ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Electron Transport Chain ◽  
Plant Mitochondria ◽  
Mitochondrial Electron Transport Chain ◽  
Oxidative Phosphorylation System ◽  
Transport Chain ◽  
Wide Range ◽  
Stress Signalling

Abstract Background Mitochondria play a diversity of physiological and metabolic roles under conditions of abiotic or biotic stress. They may be directly subjected to physico-chemical constraints, and they are also involved in integrative responses to environmental stresses through their central position in cell nutrition, respiration, energy balance and biosyntheses. In plant cells, mitochondria present various biochemical peculiarities, such as cyanide-insensitive alternative respiration, and, besides integration with ubiquitous eukaryotic compartments, their functioning must be coupled with plastid functioning. Moreover, given the sessile lifestyle of plants, their relative lack of protective barriers and present threats of climate change, the plant cell is an attractive model to understand the mechanisms of stress/organelle/cell integration in the context of environmental stress responses. Scope The involvement of mitochondria in this integration entails a complex network of signalling, which has not been fully elucidated, because of the great diversity of mitochondrial constituents (metabolites, reactive molecular species and structural and regulatory biomolecules) that are linked to stress signalling pathways. The present review analyses the complexity of stress signalling connexions that are related to the mitochondrial electron transport chain and oxidative phosphorylation system, and how they can be involved in stress perception and transduction, signal amplification or cell stress response modulation. Conclusions Plant mitochondria are endowed with a diversity of multi-directional hubs of stress signalling that lead to regulatory loops and regulatory rheostats, whose functioning can amplify and diversify some signals or, conversely, dampen and reduce other signals. Involvement in a wide range of abiotic and biotic responses also implies that mitochondrial stress signalling could result in synergistic or conflicting outcomes during acclimation to multiple and complex stresses, such as those arising from climate change.

Nippostrongylus brasiliensis: the effect of mitochondnal inhibitors on life-cycle stages

Parasitology ◽  
1984 ◽  
Vol 88 (1) ◽  
pp. 163-177 ◽  
Author(s):  
M. Fry ◽  
D. C. Jenkins
Keyword(s):  
Life Cycle ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Adult Worm ◽  
Nippostrongylus Brasiliensis ◽  
Free Living ◽  
Mitochondrial Inhibitors ◽  
Life Cycle Stages ◽  
Transport Inhibitors

SUMMARYThe effects of mitochondrial inhibitors on the in vitro development of Nippostrongylus brasiliensis have been studied in free-living and parasitic life-cycle stages. Mitochondrial inhibitors were chosen as being representative of established electron transport inhibitors and oxidative phosphorylation inhibitors and uncouplers of the classical mammalian respiratory chain. All mitochondrial inhibitors tested were highly effective in killing or retarding development of free-living stages of N. brasiliensis. Free-living stages were particularly susceptible to such inhibitors upon hatching of embryonated eggs to 1st-stage larvae. Concentrations of inhibitors effective against free-living stages were consistent with their level of inhibition against isolated mitochondria from embryonated eggs and 3rd-stage infective larvae. Results suggest an absolute requirement in the development of free-living stages for the mammalian-like respiratory chain and associated oxidative phosphorylation. Electron transport inhibitors were effective in retarding at least the initial development of 4th-stage larvae to adults, but only antimycin A and azide produced a lasting effect leading to worm death. Oxidative phosphorylation inhibitors and uncouplers were ineffective against developing parasitic stages of N. brasiliensis. Experiments on whole-worm respiration indicated that most electron transport inhibitors were able to penetrate the adult worm, but oxidative phosphorylation inhibitors were without effect on whole-worm respiration. Results suggest that the mammalian-like electron transport chain is a necessary requirement to adult N. brasiliensis, but oxidative phosphorylation in the adult worm may not be required for development and survival in vitro although it could be necessary to support the parasite in vivo.

scholarly journals Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine

Gut ◽  
1997 ◽  
Vol 41 (3) ◽  
pp. 344-353 ◽  
Author(s):  
S Somasundaram ◽  
S Rafi ◽  
J Hayllar ◽  
G Sigthorsson ◽  
M Jacob ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Small Intestine ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
In Vivo Studies ◽  
Tolerability Profile ◽  
Marker Enzyme ◽  
Subcellular Organelle

Background—The “topical” effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage.Aim—To examine the possible mechanism of the “topical” phase of damage in the small intestine.Methods—Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode.Results—The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the “topical” phase of NSAID induced damage.Conclusion—Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the “topical” phase of damage induction.

scholarly journals Mitochondrial Function in Oxidative and Glycolytic Bovine Skeletal Muscle Postmortem

2019 ◽  
Vol 3 (2) ◽  
Author(s):  
P. Ramos ◽  
L. Bell ◽  
S. Wohlgemuth ◽  
T. Scheffler
Keyword(s):  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Outer Membrane ◽  
Functional Properties ◽  
Mitochondrial Function ◽  
Complex I ◽  
Fixed Effects ◽  
Citrate Synthase ◽  
Electron Flow ◽  
Coupling Efficiency

ObjectivesMitochondrial function in postmortem muscle is affected by decreasing oxygenation. Functional properties relating to energy production and integrity of mitochondria may influence development of meat quality characteristics. Therefore, the objective was to evaluate changes in mitochondrial function in oxidative and glycolytic muscles during the first 24h postmortem.Materials and MethodsSteers (n = 6) of primarily Angus (80 to 100%) genetics were harvested at approximately 18.5 mo and 630 kg live weight. Samples from the longissimus lumborum (LL) and diaphragm (Dia) were collected at 1, 3, and 24h postmortem. Fresh-preserved muscle samples were permeabilized using saponin, and muscle bundles (2–4 mg) were transferred to a high-resolution oxygraph for respiration measurements (oxygen consumption rate, OCR, pmol/sec/mg of tissue). Samples were assessed in duplicate under hyperoxia. First, pyruvate and malate were added to support the TCA cycle and assess leak respiration. Then, ADP was added to support electron flow through complex I. The influence of glutamate on NADH production (complex I) was tested, followed by complex II activation by succinate. Integrity of the mitochondria outer membrane was tested with cytochrome c. Next, an uncoupler (FCCP) was added to force the electron transport system (ETS) to maximum capacity. Citrate synthase (CS) activity (nmol/min/mg tissue) was determined in frozen samples and used as a marker of mitochondria content. Subsequently, respiration data were normalized to CS activity (pmol/sec/U CS) to account for differences in mitochondria content. Coupling efficiency of oxidative phosphorylation was calculated as 1– (Leak/ADP-stimulated oxidative phosphorylation capacity). Raw and normalized OCR were analyzed in a randomized block design, with slaughter date as block and fixed effects of muscle, time, and the interaction. Time was considered a repeated measure.ResultsMuscle type affected (P = 0.0002) leak OCR, with Dia showing a higher rate than LL. After ADP was added, mitochondria from Dia exhibited higher OCR at all times tested and at all steps, with OCR being 4 times higher after FCCP addition. Mitochondrial content, evidenced by greater (P < 0.0001) CS activity in Dia, largely explained differences in OCR between muscles. After OCR was normalized to CS activity, the 1 and 3h postmortem OCR from Dia and LL were similar (P > 0.05). However, at 24h postmortem, OCR after ADP, glutamate, and FCCP additions were greater (P < 0.05) in Dia mitochondria. Time, but not muscle, affected cytochrome c response. At 1h postmortem, cytochrome c increased OCR by 6.6%, supporting that mitochondria outer membrane integrity is not compromised. However, cytochrome c response at 3h postmortem increased 52.4%, indicating outer membrane damage. Coupling efficiency is different between muscles (P = 0.005) with Dia exhibiting greater efficiency.ConclusionDespite inherent metabolic differences between the LL and Dia, mitochondria from both muscles are intact and coupled at 1h postmortem. However, by 24h postmortem, functional properties of LL mitochondria are reduced compared to Dia. Declining mitochondrial function may be associated with calcium overload, mitochondrial fragmentation, and protease activation.

Remodeling Ca2+ Flux By ORP4L Is Essential for Leukemia Stem Cells (LSCs) Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5257-5257
Author(s):  
Wenbin Zhong ◽  
Vesa Olkkonen ◽  
Xu Bing ◽  
Biying Zhu ◽  
Guoping Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Leukemia Stem Cells ◽  
Ip3 Receptor ◽  
Hematopoietic Stem

Abstract Acute myelogenous leukemia (AML) is one of the deadliest hematological malignancies and there is at present no efficient strategy to defeat it. New detailed insight into AML leukemia stem cells (LSCs) survival will facilitate the identification of targets for the development of new therapeutic approaches. Recent work has provided evidence that LSCs are defective in their ability to employ glycolysis, but are highly reliant on oxidative phosphorylation, and the maintenance of mitochondrial function is essential for LSCs survival. It is increasingly clear that Ca2+ released constitutively from endoplasmic reticulum (ER) is taken up by mitochondria to sustain optimal bioenergetics and cell survival. Here we report three striking findings: 1) oxysterol-binding protein (OSBP)-related protein 4 (ORP4L) is expressed in LSCs but not in normal hematopoietic stem cells (HSCs). 2) ORP4L is essential for LSC bioenergetics; It forms a complex with PLCβ3 and IP3 receptor 1 (ITPR1) to control Ca2+ release from the ER and subsequent cytosolic and mitochondrial parallel Ca2+ spike oscillations that sustain pyruvate dehydrogenase (PDH) activation and oxidative phosphorylation. 3) ORP4L inhibition eradicates LSCs in vitro and in vivo through impairment of Ca2+-dependent bioenergetics. These results suggest a novel role of ORP4L in governing Ca2+ release to sustain mitochondrial function and survival of LSCs and identify ORP4L as a putative new oncoprotein and therapeutic target for LSCs elimination. Disclosures No relevant conflicts of interest to declare.

UNCOUPLING OF OXIDATIVE PHOSPHORYLATION BY VANADATE

1966 ◽  
Vol 44 (7) ◽  
pp. 983-988 ◽  
Author(s):  
John N. Hathcock ◽  
C. H. Hill ◽  
S. B. Tove
Keyword(s):  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Adenosine Triphosphate ◽  
Adenosine Diphosphate ◽  
Liver Mitochondria ◽  
In Vitro Studies ◽  
Exchange Reactions ◽  
Uncoupling Of Oxidative Phosphorylation

The addition of ammonium metavanadate to the diet of chicks at a level to supply 25 parts per million vanadium uncoupled oxidative phosphorylation in mitochondria isolated from the livers. In vitro studies revealed that 1 mM vanadate uncoupled oxidative phosphorylation in liver mitochondria. This uncoupling was manifest whether succinate or β-hydroxybutyrate was used as the substrate, suggesting that all three phosphorylating sites associated with electron transport were uncoupled.At a concentration of 0.1 mM, vanadate increased the destruction of adenosine triphosphate by mitochondria. As the concentration of vanadate was increased the destruction of adenosine triphosphate became progressively less. The exchange reactions of adenosine triphosphate with orthophosphate and with adenosine diphosphate, catalyzed by liver mitochondria, were inhibited by 0.1 mM vanadate. These results suggest the possibility that the known toxic effects of vanadium in vivo are related to the uncoupling of oxidative phosphorylation.

scholarly journals Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner

2017 ◽  
Author(s):  
Chisato Sumi ◽  
Akihisa Okamoto ◽  
Hiromasa Tanaka ◽  
Kenichiro Nishi ◽  
Munenori Kusunoki ◽  
...  
Keyword(s):  
Cell Death ◽  
Electron Transport ◽  
Mitochondrial Function ◽  
Electron Transport Chain ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Propofol Infusion Syndrome ◽  
Metabolic Switch ◽  
Transport Chain

AbstractThe intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia in operating rooms and for sedation in intensive care units. Although there is no widely accepted definition of propofol infusion syndrome (PRIS), PRIS is defined as the development of metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, arrhythmia, and progressive cardiac failure. In vitro evidence suggests that PRIS is related to the impaired mitochondrial function. There are indications that preexisting mitochondrial disorders predispose to PRIS. However, the precise molecular mechanisms, including mitochondrial defects and a metabolic conversion by propofol, are largely unknown as yet. To elucidate the underlying cellular and molecular mechanisms of PRIS, we investigated the effects of propofol on the cellular metabolic mode and cell death. We demonstrated that clinically relevant concentrations of propofol, used within a clinically relevant exposure time, suppressed the mitochondrial function, caused the generation of reactive oxygen species, and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting complexes I and III of mitochondria. The data also indicated that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted the cell death and caspase activation induced by propofol.

Development of Impaired Cytochrome C Oxidase Activity In Apheresis Platelets During Storage

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3347-3347
Author(s):  
Yaser A. Diab ◽  
Adia Thomas ◽  
Naomi L.C. Luban ◽  
Edward Wong ◽  
Stephen J. Wagner ◽  
...  
Keyword(s):  
Steady State ◽  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Cytochrome C Oxidase ◽  
Conflicts Of Interest ◽  
Atp Depletion ◽  
In Vitro Assays ◽  
P Value ◽  
Soluble Cd40 Ligand

Abstract Abstract 3347 Background: With current storage requirements, the shelf life of platelet (PLT) products is largely limited by the development of deleterious in vitro changes associated with overall reduction in therapeutic efficacy collectively known as the “Platelet Storage Lesion” (PSL). PSL is characterized by a number of biochemical changes including lactate accumulation, bicarbonate depletion and a fall in pH. We hypothesize that these changes reflect a state of impaired oxidative phosphorylation associated with increased reliance on anaerobic glycolysis that evolves during PLT storage. In this study we evaluated the function and expression of “Cytochrome C Oxidase” (COX), a key mitochondrial enzyme in oxidative phosphorylation, with relation to several in vitro markers of PSL. The studies were performed in apheresis PLT stored for up to 7 days under standard blood bank conditions. Methods: Apheresis PLT concentrates were collected in 100% plasma using a Trima Cell Separator (CaridianBCT, Lakewood CO) to provide products with at least 3 × 1011 PLT. All products were collected in Trima® storage bags and were stored in a flatbed reciprocal agitator at 22 ± 2°C for 7 days. Multiple standard in vitro assays were performed on Days 0 (baseline measurement), 2, 4 and 7 of storage including PLT count, mean PLT volume, pH, pO2, pCO2, bicarbonate, lactate & glucose levels, aggregation and ATP release studies (ADP/Collagen), soluble CD40 ligand levels (supernatant) and total intracellular PLT ATP content. In addition, steady state COX kinetics and protein immunoblotting for COX subunits I and IV, were performed using isolated PLT mitochondria from simultaneously collected samples. Data are reported as mean ± 2 SD (n =10 experiments). One-way Analysis of Variance (ANOVA) and post-hoc Tukey's range test were used to compare data obtained at different time points. Differences were considered statistically significant only if the p value was <0.001 taking into the account that performing such large number of tests in the study increased the probability that a significant p value was incorrectly obtained by random chance. Results: PLT COX function declined significantly throughout storage (Table). Steady-state levels of COX I and IV remained essentially unchanged. This decrease in COX function paralleled progressive ATP depletion and time-dependent changes that were consistent with the development of the PSL. Conclusion: During storage of apheresis PLT for 7 days, COX function decreased progressively in association with ATP depletion indicating acquired impairment in oxidative phosphorylation. These findings suggest that bioenergetic failure is associated with PSL. Further studies are required to determine if mitochondrial dysfunction is a cause of PSL, and if it can be prevented or is amenable to therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis

2003 ◽  
Vol 160 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Jean-Ehrland Ricci ◽  
Roberta A. Gottlieb ◽  
Douglas R. Green
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Electron Transport ◽  
Cytochrome C ◽  
Mitochondrial Function ◽  
Complex I ◽  
Caspase 3 ◽  
Reactive Oxygen ◽  
Complex Iii ◽  
Oxygen Species

During apoptosis, the permeabilization of the mitochondrial outer membrane allows the release of cytochrome c, which induces caspase activation to orchestrate the death of the cell. Mitochondria rapidly lose their transmembrane potential (ΔΨm) and generate reactive oxygen species (ROS), both of which are likely to contribute to the dismantling of the cell. Here we show that both the rapid loss of ΔΨm and the generation of ROS are due to the effects of activated caspases on mitochondrial electron transport complexes I and II. Caspase-3 disrupts oxygen consumption induced by complex I and II substrates but not that induced by electron transfer to complex IV. Similarly, ΔΨm generated in the presence of complex I or II substrates is disrupted by caspase-3, and ROS are produced. Complex III activity measured by cytochrome c reduction remains intact after caspase-3 treatment. In apoptotic cells, electron transport and oxygen consumption that depends on complex I or II was disrupted in a caspase-dependent manner. Our results indicate that after cytochrome c release the activation of caspases feeds back on the permeabilized mitochondria to damage mitochondrial function (loss of ΔΨm) and generate ROS through effects of caspases on complex I and II in the electron transport chain.

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