scholarly journals A ferredoxin bridge connects the two arms of plant mitochondrial complex I

2021 ◽  
Author(s):  
Niklas Klusch ◽  
Jennifer Senkler ◽  
Özkan Yildiz ◽  
Werner Kühlbrandt ◽  
Hans-Peter Braun
Keyword(s):  
Complex I ◽  
Nadh Dehydrogenase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Nadh Dehydrogenase Subunit ◽  
Inner Mitochondrial Membrane ◽  
Main Site ◽  
Membrane Complex ◽  
The Matrix ◽  
Quinol Binding

Abstract Mitochondrial complex I is the main site for electron transfer to the respiratory chain and generates much of the proton gradient across the inner mitochondrial membrane. Complex I is composed of two arms, which form a conserved L-shape. We report the structures of the intact, 47-subunit mitochondrial complex I from Arabidopsis thaliana and the 51-subunit complex I from the green alga Polytomella sp., both at around 2.9 Å resolution. In both complexes, a heterotrimeric γ-carbonic anhydrase domain is attached to the membrane arm on the matrix side. Two states are resolved in A. thaliana complex I, with different angles between the two arms and different conformations of the ND1 (NADH dehydrogenase subunit 1) loop near the quinol binding site. The angle appears to depend on a bridge domain, which links the peripheral arm to the membrane arm and includes an unusual ferredoxin. We propose that the bridge domain participates in regulating the activity of plant complex I.

scholarly journals A ferredoxin bridge connects the two arms of plant mitochondrial complex I

2020 ◽  
Author(s):  
Niklas Klusch ◽  
Jennifer Senkler ◽  
Özkan Yildiz ◽  
Werner Kühlbrandt ◽  
Hans-Peter Braun
Keyword(s):  
Arabidopsis Thaliana ◽  
Complex I ◽  
Mitochondrial Membrane ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Inner Mitochondrial Membrane ◽  
Main Site ◽  
The Matrix ◽  
Quinol Binding ◽  
Complex I Activity

SUMMARYMitochondrial complex I is the main site for electron transfer to the respiratory chain and generates much of the proton gradient across the inner mitochondrial membrane. It is composed of two arms, which form a conserved L-shape. We report the structures of the intact, 47-subunit mitochondrial complex I from Arabidopsis thaliana and from the green alga Polytomella sp. at 3.2 and 3.3 Å resolution. In both, a heterotrimeric γ-carbonic anhydrase domain is attached to the membrane arm on the matrix side. Two states are resolved in A. thaliana complex I, with different angles between the two arms and different conformations of the ND1 loop near the quinol binding site. The angle appears to depend on a bridge domain, which links the peripheral arm to the membrane arm and includes an unusual ferredoxin. We suggest that the bridge domain regulates complex I activity.One sentence summaryThe activity of complex I depends on the angel between its two arms, which, in plants, is adjusted by a protein bridge that includes an unusual ferredoxin.The authors responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) are: Hans-Peter Braun ([email protected]) and Werner Kühlbrandt ([email protected]).

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.

scholarly journals Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
William W Wheaton ◽  
Samuel E Weinberg ◽  
Robert B Hamanaka ◽  
Saul Soberanes ◽  
Lucas B Sullivan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Cellular Respiration ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Human Cancer Cells

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.

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.

Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I

Nature ◽  
2004 ◽  
Vol 432 (7017) ◽  
pp. 618-622 ◽  
Author(s):  
Ivan Hrdy ◽  
Robert P. Hirt ◽  
Pavel Dolezal ◽  
Lucie Bardonová ◽  
Peter G. Foster ◽  
...  
Keyword(s):  
Complex I ◽  
Nadh Dehydrogenase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex

scholarly journals Novel mitochondrial complex I-inhibiting peptides restrain NADH dehydrogenase activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yao-Peng Xue ◽  
Mou-Chieh Kao ◽  
Chung-Yu Lan
Keyword(s):  
Antimicrobial Peptides ◽  
Complex I ◽  
Fungal Pathogens ◽  
Nadh Dehydrogenase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Human Fungal Pathogen ◽  
New Class ◽  
Transport Chain ◽  
Nadh Dehydrogenases

Abstract The emergence of drug-resistant fungal pathogens is becoming increasingly serious due to overuse of antifungals. Antimicrobial peptides have potent activity against a broad spectrum of pathogens, including fungi, and are considered a potential new class of antifungals. In this study, we examined the activities of the newly designed peptides P-113Du and P-113Tri, together with their parental peptide P-113, against the human fungal pathogen Candida albicans. The results showed that these peptides inhibit mitochondrial complex I, specifically NADH dehydrogenase, of the electron transport chain. Moreover, P-113Du and P-113Tri also block alternative NADH dehydrogenases. Currently, most inhibitors of the mitochondrial complex I are small molecules or artificially-designed antibodies. Here, we demonstrated novel functions of antimicrobial peptides in inhibiting the mitochondrial complex I of C. albicans, providing insight in the development of new antifungal agents.

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