scholarly journals Cork-in-bottle mechanism of inhibitor binding to mammalian complex I

2021 ◽  
Vol 7 (20) ◽  
pp. eabg4000
Author(s):  
Injae Chung ◽  
Riccardo Serreli ◽  
Jason B. Cross ◽  
M. Emilia Di Francesco ◽  
Joseph R. Marszalek ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Structural Motif ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Inhibitor Binding ◽  
Mechanism Of Inhibition ◽  
Specific Complex ◽  
A Chain

Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo–electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a “chain” of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.

Opening mitoKATP increases superoxide generation from complex I of the electron transport chain

2006 ◽  
Vol 291 (5) ◽  
pp. H2067-H2074 ◽  
Author(s):  
Anastasia Andrukhiv ◽  
Alexandre D. Costa ◽  
Ian C. West ◽  
Keith D. Garlid
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Liver Mitochondria ◽  
Isolated Rat Heart ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Ros Production ◽  
Transport Chain

Opening the mitochondrial ATP-sensitive K+ channel (mitoKATP) increases levels of reactive oxygen species (ROS) in cardiomyocytes. This increase in ROS is necessary for cardioprotection against ischemia-reperfusion injury; however, the mechanism of mitoKATP-dependent stimulation of ROS production is unknown. We examined ROS production in suspensions of isolated rat heart and liver mitochondria, using fluorescent probes that are sensitive to hydrogen peroxide. When mitochondria were treated with the KATP channel openers diazoxide or cromakalim, their ROS production increased by 40–50%, and this effect was blocked by 5-hydroxydecanoate. ROS production exhibited a biphasic dependence on valinomycin concentration, with peak production occurring at valinomycin concentrations that catalyze about the same K+ influx as KATP channel openers. ROS production decreased with higher concentrations of valinomycin and with all concentrations of a classical protonophoretic uncoupler. Our studies show that the increase in ROS is due specifically to K+ influx into the matrix and is mediated by the attendant matrix alkalinization. Myxothiazol stimulated mitoKATP-dependent ROS production, whereas rotenone had no effect. This indicates that the superoxide originates in complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain.

scholarly journals NDUFAB1 Protects Heart by Coordinating Mitochondrial Respiratory Complex and Supercomplex Assembly

2018 ◽  
Author(s):  
Tingting Hou ◽  
Rufeng Zhang ◽  
Chongshu Jian ◽  
Wanqiu Ding ◽  
Yanru Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Common Mechanism ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Energy Metabolism ◽  
Ros Metabolism ◽  
Mitochondrial Respiratory Complex ◽  
Specific Deletion

AbstractThe impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is emerging as a common mechanism in diseases of organs with a high demand for energy, such as the heart. Building a more robust cellular powerhouse holds promise for protecting these organs in stressful conditions. Here, we demonstrate that NDUFAB1 (NADH:ubiquinone oxidoreductase subunit AB1), acts as a powerful cardio-protector by enhancing mitochondrial energy biogenesis. In particular, NDUFAB1 coordinates the assembly of respiratory complexes I, II, and III and supercomplexes, conferring greater capacity and efficiency of mitochondrial energy metabolism. Cardiac-specific deletion of Ndufab1 in mice caused progressive dilated cardiomyopathy associated with defective bioenergetics and elevated ROS levels, leading to heart failure and sudden death. In contrast, transgenic overexpression of Ndufab1 effectively enhanced mitochondrial bioenergetics and protected the heart against ischemia-reperfusion injury. Our findings identify NDUFAB1 as a central endogenous regulator of mitochondrial energy and ROS metabolism and thus provide a potential therapeutic target for the treatment of heart failure and other mitochondrial bioenergetics-centered diseases.

scholarly journals Nitrite attenuates mitochondrial impairment and vascular permeability induced by ischemia-reperfusion injury in the lung

2020 ◽  
Vol 318 (4) ◽  
pp. L580-L591
Author(s):  
Ajay Kumar ◽  
Kentaro Noda ◽  
Brian Philips ◽  
Murugesan Velayutham ◽  
Donna B. Stolz ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pulmonary Vascular Permeability ◽  
Ultrastructural Studies ◽  
Mitochondrial Impairment ◽  
Complex I Activity

Primary graft dysfunction (PGD) is directly related to ischemia-reperfusion (I/R) injury and a major obstacle in lung transplantation (LTx). Nitrite ([Formula: see text]), which is reduced in vivo to form nitric oxide (NO), has recently emerged as an intrinsic signaling molecule with a prominent role in cytoprotection against I/R injury. Using a murine model, we provide the evidence that nitrite mitigated I/R-induced injury by diminishing infiltration of immune cells in the alveolar space, reducing pulmonary edema, and improving pulmonary function. Ultrastructural studies support severe mitochondrial impairment in the lung undergoing I/R injury, which was significantly protected by nitrite treatment. Nitrite also abrogated the increased pulmonary vascular permeability caused by I/R. In vitro, hypoxia-reoxygenation (H/R) exacerbated cell death in lung epithelial and microvascular endothelial cells. This contributed to mitochondrial dysfunction as characterized by diminished complex I activity and mitochondrial membrane potential but increased mitochondrial reactive oxygen species (mtROS). Pretreatment of cells with nitrite robustly attenuated mtROS production through modulation of complex I activity. These findings illustrate a potential novel mechanism in which nitrite protects the lung against I/R injury by regulating mitochondrial bioenergetics and vascular permeability.

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 Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3

2017 ◽  
Vol 114 (45) ◽  
pp. 11908-11913 ◽  
Author(s):  
Hengxun Hu ◽  
Jinliang Nan ◽  
Yong Sun ◽  
Dan Zhu ◽  
Changchen Xiao ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Oxygen Consumption ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Cell Protection ◽  
Causative Relationship ◽  
R Process ◽  
And Function

The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors ofN,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2level in the cytosol, but not in the mitochondria. Importantly, increased H2O2served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.

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