scholarly journals Cytochrome c Oxidase Is Required for the Assembly/Stability of Respiratory Complex I in Mouse Fibroblasts

2006 ◽  
Vol 26 (13) ◽  
pp. 4872-4881 ◽  
Author(s):  
Francisca Diaz ◽  
Hirokazu Fukui ◽  
Sofia Garcia ◽  
Carlos T. Moraes
Keyword(s):  
Complex I ◽  
Residual Activity ◽  
Complex Iv ◽  
Farnesyl Transferase ◽  
Respiratory Complex ◽  
Dividing Cells ◽  
Mouse Cells ◽  
Respiratory Complex I ◽  
Complex I Assembly ◽  
Respiratory Deficient

ABSTRACT Cytochrome c oxidase (COX) biogenesis requires COX10, which encodes a protoheme:heme O farnesyl transferase that participates in the biosynthesis of heme a. We created COX10 knockout mouse cells that lacked cytochrome aa3 , were respiratory deficient, had no detectable complex IV activity, and were unable to assemble COX. Unexpectedly, the levels of respiratory complex I were markedly reduced in COX10 knockout clones. Pharmacological inhibition of COX did not affect the levels of complex I, and transduction of knockout cells with lentivirus expressing wild-type or mutant COX10 (retaining residual activity) restored complex I to normal levels. Pulse-chase experiments could not detect newly assembled complex I, suggesting that either COX is required for assembly of complex I or the latter is quickly degraded. These results suggest that in rapidly dividing cells, complex IV is required for complex I assembly or stability.

scholarly journals High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease

2019 ◽  
Vol 5 (12) ◽  
pp. eaax9484 ◽  
Author(s):  
Kristian Parey ◽  
Outi Haapanen ◽  
Vivek Sharma ◽  
Harald Köfeler ◽  
Thomas Züllig ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Membrane ◽  
Electrochemical Gradient ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Complex ◽  
Access Path ◽  
Respiratory Complex I ◽  
Assembly Intermediate ◽  
The One ◽  
Complex I Assembly

Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I–linked disease and complex I assembly in the inner mitochondrial membrane.

Deciphering the respiratory Complex I assembly pathway

Mitochondrion ◽  
2013 ◽  
Vol 13 (6) ◽  
pp. 917
Author(s):  
Rasika Vartak ◽  
Janice Deng ◽  
Yidong Bai
Keyword(s):  
Complex I ◽  
Respiratory Complex ◽  
Assembly Pathway ◽  
Respiratory Complex I ◽  
Complex I Assembly

scholarly journals Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1840
Author(s):  
Camilo Febres-Molina ◽  
Jorge A. Aguilar-Pineda ◽  
Pamela L. Gamero-Begazo ◽  
Haruna L. Barazorda-Ccahuana ◽  
Diego E. Valencia ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Complex I ◽  
Binding Free Energy ◽  
Biological Activities ◽  
Experimental Studies ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Mitochondrial Respiratory

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

scholarly journals A salvage pathway maintains highly functional respiratory complex I

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Karolina Szczepanowska ◽  
Katharina Senft ◽  
Juliana Heidler ◽  
Marija Herholz ◽  
Alexandra Kukat ◽  
...  
Keyword(s):  
Complex I ◽  
Salvage Pathway ◽  
Respiratory Complex ◽  
Respiratory Complex I
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