Structural basis for a complex I mutation that blocks pathological ROS production
Authors
Kula-Alwar, Duvaraka
Viscomi, Carlo
James, Andrew M.
Publication Date
2021-01-29Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
12
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
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Yin, Z., Burger, N., Kula-Alwar, D., Aksentijević, D., Bridges, H. R., Prag, H. A., Grba, D. N., et al. (2021). Structural basis for a complex I mutation that blocks pathological ROS production. Nature Communications, 12 (1) https://doi.org/10.1038/s41467-021-20942-w
Description
Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187
Abstract
Abstract: Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.
Keywords
Article, /631/45/56, /631/45/535/1258/1259, /631/57/1464, /9, /101, /101/28, article
Identifiers
s41467-021-20942-w, 20942
External DOI: https://doi.org/10.1038/s41467-021-20942-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/316863
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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