Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli.
Bioenergetics
Complex I
LHON
Mitochondria
Mutations
NADH dehydrogenase
Journal
Mitochondrion
ISSN: 1872-8278
Titre abrégé: Mitochondrion
Pays: Netherlands
ID NLM: 100968751
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
24
01
2022
revised:
21
02
2022
accepted:
15
03
2022
pubmed:
21
3
2022
medline:
27
4
2022
entrez:
20
3
2022
Statut:
ppublish
Résumé
Respiratory Complex I is the site of a large fraction of the mutations that appear to cause mitochondrial disease. Seven of its subunits are mitochondrially encoded, and therefore, such mutants are particularly difficult to construct in cell-culture model systems. We have selected 13 human clinical mutations found in ND2, ND3, ND4, ND4L, ND5 and ND6 that are generally found at subunit interfaces, and not in critical residues. These mutations have been modeled in E. coli subunits of Complex I, nuoN, nuoA, nuoM, nuoK, nuoL, and nuoJ, respectively. All mutants were expressed from a plasmid encoding the entire nuo operon, and membrane vesicles were analyzed for deamino-NADH oxidase activity, and proton translocation activity. ND5 mutants were also analyzed using a time-delayed expression system, recently described by this lab. Other mutants were analyzed for the ability to associate in subcomplexes, after expression of subsets of the genes. For most mutants there was a positive correlation between those that were previously determined to be pathogenic, or likely to be pathogenic, and those that we found with compromised Complex I activity or subunit interactions in E. coli. In conclusion, this approach provides another way to explore the deleterious effects of human mitochondrial mutations, and it can contribute to molecular understanding of such mutations.
Identifiants
pubmed: 35306226
pii: S1567-7249(22)00022-8
doi: 10.1016/j.mito.2022.03.001
pmc: PMC9035099
mid: NIHMS1790804
pii:
doi:
Substances chimiques
Protein Subunits
0
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-72Subventions
Organisme : NIGMS NIH HHS
ID : R15 GM126507
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
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