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Structural basis fo...
Structural basis for a complex I mutation that blocks pathological ROS production
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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2021-01-29
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Springer Science and Business Media LLC,2021
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LIBRIS-ID:oai:gup.ub.gu.se/304755
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https://gup.ub.gu.se/publication/304755URI
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https://doi.org/10.1038/s41467-021-20942-wDOI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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. © 2021, The Author(s).
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Burger, N.
(author)
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Kula-Alwar, D.
(author)
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Aksentijević, D.
(author)
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Bridges, H. R.
(author)
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Prag, H. A.
(author)
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Grba, D. N.
(author)
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Viscomi, C.
(author)
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James, A. M.
(author)
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Mottahedin, AminGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xmotam
(author)
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Krieg, T.
(author)
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Murphy, M. P.
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Hirst, J.
(author)
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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för fysiologi
(creator_code:org_t)
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In:Nature Communications: Springer Science and Business Media LLC12:12041-1723
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Yin, Z.
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Burger, N.
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Kula-Alwar, D.
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Aksentijević, D.
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Bridges, H. R.
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Prag, H. A.
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show more...
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Grba, D. N.
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Viscomi, C.
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James, A. M.
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Mottahedin, Amin
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Krieg, T.
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Murphy, M. P.
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Hirst, J.
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University of Gothenburg