scholarly journals Dopamine-derived Dopaminochrome Promotes H2O2Release at Mitochondrial Complex I

2005 ◽  
Vol 280 (16) ◽  
pp. 15587-15594 ◽  
Author(s):  
Franco Zoccarato ◽  
Paola Toscano ◽  
Adolfo Alexandre
Keyword(s):  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Brain Mitochondria ◽  
Oxidation Products ◽  
Mitochondrial Complex I ◽  
Redox Cycle ◽  
Mitochondrial Complex ◽  
Low Concentrations ◽  
Symptoms And Signs ◽  
Primary Action

Inhibitors of Complex I of the mitochondrial respiratory chain, such as rotenone, promote Parkinson disease-like symptoms and signs of oxidative stress. Dopamine (DA) oxidation products may be implicated in such a process. We show here that theo-quinone dopaminochrome (DACHR), a relatively stable DA oxidation product, promotes concentration (0.1–0.2 μm)- and respiration-dependent generation of H2O2at Complex I in brain mitochondria, with further stimulation by low concentrations of rotenone (5–30 nm). The rotenone effect required that contaminating Ca2+(8–10 μm) was not removed. DACHR apparently extracts an electron from the constitutively autoxidizable site in Complex I, producing a semiquinone, which then transfers an electron to O2, generating\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document}and then H2O2. Mitochondrial removal of H2O2monoamine, formed by either oxidase activity or DACHR, was performed largely by glutathione peroxidase and glutathione reductase, which were negatively regulated by low intramitochondrial Ca2+levels. Thus, the H2O2formed accumulated in the medium if contaminating Ca2+was present; in the absence of Ca2+, H2O2was completely removed if it originated from monoamine oxidase, but was less completely removed if it originated from DACHR. We propose that the primary action of rotenone is to promote extracellular\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document}release via activation of NADPH oxidase in the microglia. In turn,\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document}oxidizes DA to DACHR extracellularly. (The reaction is favored by the lack of GSH, which would otherwise preferably produce GSH adducts of dopaminoquinone.) Once formed, DACHR (which is resistant to GSH) enters neurons to activate the rotenone-stimulated redox cycle described.

scholarly journals Mechanistic insight from the crystal structure of mitochondrial complex I

Science ◽  
2015 ◽  
Vol 347 (6217) ◽  
pp. 44-49 ◽  
Author(s):  
Volker Zickermann ◽  
Christophe Wirth ◽  
Hamid Nasiri ◽  
Karin Siegmund ◽  
Harald Schwalbe ◽  
...  
Keyword(s):  
Complex I ◽  
Protein Complexes ◽  
Active Form ◽  
Mitochondrial Respiratory Chain ◽  
Structural Rearrangement ◽  
Proton Pumping ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Degenerative Disorders ◽  
Pumping Units

Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the “deactive” form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.

scholarly journals Specific features and assembly of the plant mitochondrial complex I revealed by cryo-EM

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Heddy Soufari ◽  
Camila Parrot ◽  
Lauriane Kuhn ◽  
Florent Waltz ◽  
Yaser Hashem
Keyword(s):  
Carbonic Anhydrase ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Entry Site ◽  
Lipid Complex ◽  
Maturation Factor ◽  
Specific Complex

Abstract Mitochondria are the powerhouses of eukaryotic cells and the site of essential metabolic reactions. Complex I or NADH:ubiquinone oxidoreductase is the main entry site for electrons into the mitochondrial respiratory chain and constitutes the largest of the respiratory complexes. Its structure and composition vary across eukaryote species. However, high resolution structures are available only for one group of eukaryotes, opisthokonts. In plants, only biochemical studies were carried out, already hinting at the peculiar composition of complex I in the green lineage. Here, we report several cryo-electron microscopy structures of the plant mitochondrial complex I. We describe the structure and composition of the plant respiratory complex I, including the ancestral mitochondrial domain composed of the carbonic anhydrase. We show that the carbonic anhydrase is a heterotrimeric complex with only one conserved active site. This domain is crucial for the overall stability of complex I as well as a peculiar lipid complex composed of cardiolipin and phosphatidylinositols. Moreover, we also describe the structure of one of the plant-specific complex I assembly intermediates, lacking the whole PD module, in presence of the maturation factor GLDH. GLDH prevents the binding of the plant specific P1 protein, responsible for the linkage of the PP to the PD module.

scholarly journals Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

2016 ◽  
Vol 113 (46) ◽  
pp. 13063-13068 ◽  
Author(s):  
Irene Lopez-Fabuel ◽  
Juliette Le Douce ◽  
Angela Logan ◽  
Andrew M. James ◽  
Gilles Bonvento ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Complex I ◽  
Structural Organization ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Mitochondrial Ros ◽  
Complex I Assembly

Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.

scholarly journals Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0144290 ◽  
Author(s):  
Naïg Gueguen ◽  
Valérie Desquiret-Dumas ◽  
Géraldine Leman ◽  
Stéphanie Chupin ◽  
Stéphanie Baron ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex I ◽  
Brain Mitochondria ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Aged Mice

scholarly journals Specific features and assembly of the plant mitochondrial complex I revealed by cryo-EM

2020 ◽  
Author(s):  
Heddy Soufari ◽  
Camila Parrot ◽  
Lauriane Kuhn ◽  
Florent Waltz ◽  
Yaser Hashem
Keyword(s):  
Carbonic Anhydrase ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Eukaryotic Cells ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Entry Site ◽  
Lipid Complex ◽  
Additional Domain

AbstractMitochondria are the powerhouses of eukaryotic cells and the site of essential metabolic reactions. Their main purpose is to maintain the high ATP/ADP ratio that is required to fuel the countless biochemical reactions taking place in eukaryotic cells1. This high ATP/ADP ratio is maintained through oxidative phosphorylation (OXPHOS). Complex I or NADH:ubiquinone oxidoreductase is the main entry site for electrons into the mitochondrial respiratory chain and constitutes the largest of the respiratory complexes2. Its structure and composition varies across eukaryotes species. However, high resolution structures are available only for one group of eukaryotes, opisthokonts3–6. In plants, only biochemical studies were carried out, already hinting the peculiar composition of complex I in the green lineage. Here, we report several cryo-electron microscopy structures of the plant mitochondrial complex I at near-atomic resolution. We describe the structure and composition of the plant complex I including the plant-specific additional domain composed by carbonic anhydrase proteins. We show that the carbonic anhydrase is an heterotrimeric complex with only one conserved active site. This domain is crucial for the overall stability of complex I as well as a peculiar lipid complex composed cardiolipin and phosphatidylinositols. Moreover we also describe the structure of one of the plant-specific complex I assembly intermediate, lacking the whole PD module, in presence of the maturation factor GLDH. GLDH prevents the binding of the plant specific P1 protein, responsible for the linkage of the PP to the PD module. Finally, as the carbonic anhydrase domain is likely to be associated with complex I from numerous other known eukaryotes, we propose that our structure unveils an ancestral-like organization of mitochondrial complex I.

scholarly journals Inhibition of Mitochondrial Complex I Impairs Release of α-Galactosidase by Jurkat Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4349
Author(s):  
Jonathan Lambert ◽  
Steven Howe ◽  
Ahad Rahim ◽  
Derek Burke ◽  
Simon Heales
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Jurkat Cells ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Mitochondrial Respiratory Chain Activity ◽  
Respiratory Chain Activity ◽  
Mitochondrial Respiratory

Fabry disease (FD) is caused by mutations in the GLA gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment. In view of the loss of mitochondrial function reported in FD, we have considered here the impact of loss of mitochondrial respiratory chain activity on the ability of a GLA lentiviral vector to increase cellular α-gal-A activity and participate in cross correction. Jurkat cells were used in this study and were exposed to increasing viral copies. Intracellular and extracellular enzyme activities were then determined; this in the presence or absence of the mitochondrial complex I inhibitor, rotenone. The ability of cells to take up released enzyme was also evaluated. Increasing transgene copies was associated with increasing intracellular α-gal-A activity but this was associated with an increase in Km. Release of enzyme and cellular uptake was also demonstrated. However, in the presence of rotenone, enzyme release was inhibited by 37%. Excessive enzyme generation may result in a protein with inferior kinetic properties and a background of compromised mitochondrial function may impair the cross correction process.

scholarly journals Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury

2017 ◽  
Vol 37 (12) ◽  
pp. 3649-3658 ◽  
Author(s):  
Anna Stepanova ◽  
Anja Kahl ◽  
Csaba Konrad ◽  
Vadim Ten ◽  
Anatoly S Starkov ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Brain Ischemia ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Brain Mitochondria ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Reverse Electron Transfer ◽  
Novel Target

Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+. We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme's flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process.

scholarly journals Deactivation of mitochondrial complex I after hypoxia–ischemia in the immature brain

2018 ◽  
Vol 39 (9) ◽  
pp. 1790-1802 ◽  
Author(s):  
Anna Stepanova ◽  
Csaba Konrad ◽  
Sergio Guerrero-Castillo ◽  
Giovanni Manfredi ◽  
Susan Vannucci ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Immature Brain ◽  
Mitochondrial Oxygen Consumption ◽  
Mitochondrial Target ◽  
Enzyme Complexes

Mortality from perinatal hypoxic–ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on H2O2 release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome c oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy.

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