Point mutations in various complex I subunits derived from mitochondrial DNA (mtDNA) can also result in Leber's Hereditary Optic Neuropathy. This review evaluates extant data on the mechanisms of energy transduction and superoxide production by complex I, discusses contemporary mechanistic models, and explores how mechanistic studies may contribute to understanding the roles of complex I dysfunctions in human diseases. Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I. doi: 10.1146/annurev-biochem-070511-103700. Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. The enzyme oxidizes NADH transferring electrons to Ubiquinone (Coenzyme Q, CoQ), a lipid soluble electron carrier embedded in the lipid bilayer of the inner mitochondrial membrane. 2020 Dec 23;11:608550. doi: 10.3389/fpls.2020.608550.  |  Architecture of bacterial respiratory chains. Functional Water Wires Catalyze Long-Range Proton Pumping in the Mammalian Respiratory Complex I. It is also a major contributor to cellular production of reactive oxygen species. Therefore, we further investigated this interaction using genetic approaches to determine the biological significance. Structure of the respiratory MBS complex reveals iron-sulfur cluster catalyzed sulfane sulfur reduction in ancient life. COVID-19 is an emerging, rapidly evolving situation. Xiu Z, Peng L, Wang Y, Yang H, Sun F, Wang X, Cao SK, Jiang R, Wang L, Chen BY, Tan BC. There is some evidence that complex I defects may play a role in the etiology of Parkinson's disease, perhaps because of reactive oxygen species (complex I can, like complex III, leak electrons to oxygen, forming highly toxic superoxide). Of particular functional importance are the flavin prosthetic group (FMN) and eight iron-sulfur clusters (FeS). The deactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and peroxynitrite. [14][17] Alternative theories suggest a "two stroke mechanism" where each reduction step (semiquinone and ubiquinol) results in a stroke of two protons entering the intermembrane space. Challenges in elucidating structure and mechanism of proton pumping NADH:ubiquinone oxidoreductase (complex I). 2013 Jun 11;52(23):4048-55. doi: 10.1021/bi3016873. All relevant terms must be followed. [10] The high reduction potential of the N2 cluster and the relative proximity of the other clusters in the chain enable efficient electron transfer over long distance in the protein (with transfer rates from NADH to N2 iron-sulfur cluster of about 100 μs). … In mammals, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. [1] Complex I is the largest and most complicated enzyme of the electron transport chain.[2]. [24] All thirteen of the E. coli proteins, which comprise NADH dehydrogenase I, are encoded within the nuo operon, and are homologous to mitochondrial complex I subunits. Mitochondria in Complex Diseases will explore the impact of these cellular powerhouses in physiology and medicine. 192, 2, p. 225-229 5 p. Research output: Contribution to journal › Article › Academic › peer-review We explain how they got this title, and outline other important roles that they carry out. [16] Further electron paramagnetic resonance studies of the electron transfer have demonstrated that most of the energy that is released during the subsequent CoQ reduction is on the final ubiquinol formation step from semiquinone, providing evidence for the "single stroke" H+ translocation mechanism (i.e. NIH When mitochondria are energized by a combination of complex I (malate-glutamate) and complex II (succinate) substrates and in the absence of specific inhibitors of the complexes, ROS production is considered as mainly derived from reverse electron transport (RET) at site I Q (A). A recent study used electron paramagnetic resonance (EPR) spectra and double electron-electron resonance (DEER) to determine the path of electron transfer through the iron-sulfur complexes, which are located in the hydrophilic domain. Complex I contains a ubiquinone binding pocket at the interface of the 49-kDa and PSST subunits. Complex I is an L-shaped integral membrane protein. 2021 Jan 15. doi: 10.1007/s10709-020-00112-4. Close to iron-sulfur cluster N2, the proposed immediate electron donor for ubiquinone, a highly conserved tyrosine constitutes a critical element of the quinone reduction site. The NDI1 gene encoding rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria was cotransfected into the complex I-deficient Chinese hamster CCL16-B2 cells. 2009 Dec 23;425(2):327-39. doi: 10.1042/BJ20091382. It couples electron transfer from NADH to ubiquinone with proton translocation across the energy-transducing inner membrane, providing electrons for … Zickermann V, Dröse S, Tocilescu MA, Zwicker K, Kerscher S, Brandt U. J Bioenerg Biomembr. Complex I Is Visible in Tomographic Volumes. [46] Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, electron-transferring flavoprotein or dihydroorotate dehydrogenase in mammalian mitochondria) pass through complex I to reduce NAD+ to NADH, driven by the inner mitochondrial membrane potential electric potential. Escherichia coli complex I (NADH dehydrogenase) is capable of proton translocation in the same direction to the established Δψ, showing that in the tested conditions, the coupling ion is H+. Epub 2015 Dec 22. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.[38]. [6] Na+ transport in the opposite direction was observed, and although Na+ was not necessary for the catalytic or proton transport activities, its presence increased the latter. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. [47] This can take place during tissue ischaemia, when oxygen delivery is blocked. [39] Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively. Respiratory chain supercomplexes were visualized in situ by cryo-ET of mitochondrial membranes from bovine heart, the yeast Y. lipolytica, and the plant Asparagus officinalis.To improve contrast, matrix proteins of bovine and yeast mitochondria were removed by osmotic shock, while asparagus mitochondria underwent spontaneous disruption. Front Plant Sci. 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