scholarly journals Large scale atomistic simulations unveil key role of ubiquinone dynamics in proton pumping by mitochondrial complex I

2018 ◽  
Vol 1859 ◽  
pp. e10
Author(s):  
Vivek Sharma ◽  
Outi Haapanen
Keyword(s):  
Complex I ◽  
Large Scale ◽  
Proton Pumping ◽  
Atomistic Simulations ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex

scholarly journals Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Etienne Galemou Yoga ◽  
Kristian Parey ◽  
Amina Djurabekova ◽  
Outi Haapanen ◽  
Karin Siegmund ◽  
...  
Keyword(s):  
Complex I ◽  
Essential Role ◽  
Structural Changes ◽  
Proton Pumping ◽  
Mitochondrial Complex I ◽  
Coupling Mechanism ◽  
Mitochondrial Complex ◽  
Inner Mitochondrial Membrane ◽  
Accessory Subunit

AbstractRespiratory complex I catalyzes electron transfer from NADH to ubiquinone (Q) coupled to vectorial proton translocation across the inner mitochondrial membrane. Despite recent progress in structure determination of this very large membrane protein complex, the coupling mechanism is a matter of ongoing debate and the function of accessory subunits surrounding the canonical core subunits is essentially unknown. Concerted rearrangements within a cluster of conserved loops of central subunits NDUFS2 (β1-β2S2 loop), ND1 (TMH5-6ND1 loop) and ND3 (TMH1-2ND3 loop) were suggested to be critical for its proton pumping mechanism. Here, we show that stabilization of the TMH1-2ND3 loop by accessory subunit LYRM6 (NDUFA6) is pivotal for energy conversion by mitochondrial complex I. We determined the high-resolution structure of inactive mutant F89ALYRM6 of eukaryotic complex I from the yeast Yarrowia lipolytica and found long-range structural changes affecting the entire loop cluster. In atomistic molecular dynamics simulations of the mutant, we observed conformational transitions in the loop cluster that disrupted a putative pathway for delivery of substrate protons required in Q redox chemistry. Our results elucidate in detail the essential role of accessory subunit LYRM6 for the function of eukaryotic complex I and offer clues on its redox-linked proton pumping mechanism.

scholarly journals Paracoccus denitrificans: a genetically tractable model system for studying respiratory complex I

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Owen D. Jarman ◽  
Olivier Biner ◽  
John J. Wright ◽  
Judy Hirst
Keyword(s):  
Complex I ◽  
Paracoccus Denitrificans ◽  
Model System ◽  
Proton Pumping ◽  
Model Systems ◽  
Metabolic Enzyme ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Inner Mitochondrial Membrane

AbstractMitochondrial complex I (NADH:ubiquinone oxidoreductase) is a crucial metabolic enzyme that couples the free energy released from NADH oxidation and ubiquinone reduction to the translocation of four protons across the inner mitochondrial membrane, creating the proton motive force for ATP synthesis. The mechanism by which the energy is captured, and the mechanism and pathways of proton pumping, remain elusive despite recent advances in structural knowledge. Progress has been limited by a lack of model systems able to combine functional and structural analyses with targeted mutagenic interrogation throughout the entire complex. Here, we develop and present the α-proteobacterium Paracoccus denitrificans as a suitable bacterial model system for mitochondrial complex I. First, we develop a robust purification protocol to isolate highly active complex I by introducing a His6-tag on the Nqo5 subunit. Then, we optimize the reconstitution of the enzyme into liposomes, demonstrating its proton pumping activity. Finally, we develop a strain of P. denitrificans that is amenable to complex I mutagenesis and create a catalytically inactive variant of the enzyme. Our model provides new opportunities to disentangle the mechanism of complex I by combining mutagenesis in every subunit with established interrogative biophysical measurements on both the soluble and membrane bound enzymes.

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 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 Large-Scale Deletion and Point Mutations of the Nuclear NDUFV1 and NDUFS1 Genes in Mitochondrial Complex I Deficiency

2001 ◽  
Vol 68 (6) ◽  
pp. 1344-1352 ◽  
Author(s):  
Paule Bénit ◽  
Dominique Chretien ◽  
Nohman Kadhom ◽  
Pascale de Lonlay-Debeney ◽  
Valérie Cormier-Daire ◽  
...  
Keyword(s):  
Complex I ◽  
Large Scale ◽  
Point Mutations ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Complex I Deficiency

scholarly journals The opposite prognostic effect of NDUFS1 and NDUFS8 in lung cancer reflects the oncojanus role of mitochondrial complex I

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Chia-Yi Su ◽  
Yu-Chan Chang ◽  
Chih-Jen Yang ◽  
Ming-Shyan Huang ◽  
Michael Hsiao
Keyword(s):  
Lung Cancer ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Prognostic Effect
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