The multitude of iron–sulfur clusters in respiratory complex I

ABSTRACT Respiratory complex I (NADH:ubiquinone oxidoreductase) is a large mitochondrial inner membrane enzyme consisting of 45 subunits and 8 iron-sulfur (Fe/S) clusters. While complex I dysfunction is the most common reason for mitochondrial diseases, the assembly of complex I and its Fe/S cofactors remains elusive. Here, we identify the human mitochondrial P-loop NTPase, designated huInd1, that is critically required for the assembly of complex I. huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion. Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong decreases in complex I protein and activity levels, remodeling of respiratory supercomplexes, and alteration of mitochondrial morphology. In addition, huInd1 depletion resulted in massive decreases in several subunits (NDUFS1, NDUFV1, NDUFS3, and NDUFA13) of the peripheral arm of complex I, with the concomitant appearance of a 450-kDa subcomplex representing part of the membrane arm. By a novel radiolabeling technique, the amount of iron associated with complex I was also shown to reflect the dependence of this enzyme on huInd1 for assembly. Together, these data identify huInd1 as a new assembly factor for human respiratory complex I with a possible role in the delivery of one or more Fe/S clusters to complex I subunits.

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Faculty Opinions recommendation of Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1031528.365699 ◽

2006 ◽

Author(s):

Carola Hunte

Keyword(s):

Complex I ◽

Thermus Thermophilus ◽

Respiratory Complex ◽

Respiratory Complex I ◽

Hydrophilic Domain

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Faculty Opinions recommendation of The architecture of respiratory complex I.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3375956.3066054 ◽

2010 ◽

Author(s):

Nathan Nelson

Keyword(s):

Complex I ◽

Respiratory Complex ◽

Respiratory Complex I

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Faculty Opinions recommendation of The architecture of respiratory complex I.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3375956.4039088 ◽

2010 ◽

Author(s):

Petra Fromme ◽

Ingo Grotjohann

Keyword(s):

Complex I ◽

Respiratory Complex ◽

Respiratory Complex I

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Faculty Opinions recommendation of Crystal structure of the entire respiratory complex I.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717979709.793473492 ◽

2013 ◽

Author(s):

Ramón Serrano

Keyword(s):

Crystal Structure ◽

Complex I ◽

Respiratory Complex ◽

Respiratory Complex I

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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 ◽

10.3390/polym13111840 ◽

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.

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