Structural basis for a complex I mutation that blocks pathological ROS production.

Autor: Yin Z; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Burger N; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Kula-Alwar D; Department of Medicine, University of Cambridge, Cambridge, UK., Aksentijević D; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK., Bridges HR; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Prag HA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Grba DN; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Viscomi C; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Department of Biomedical Sciences, University of Padova via Ugo Bassi 58/B, Padova, 35131, Italy., James AM; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Mottahedin A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK.; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Krieg T; Department of Medicine, University of Cambridge, Cambridge, UK., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. mpm@mrc-mbu.cam.ac.uk.; Department of Medicine, University of Cambridge, Cambridge, UK. mpm@mrc-mbu.cam.ac.uk., Hirst J; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. jh@mrc-mbu.cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 29; Vol. 12 (1), pp. 707. Date of Electronic Publication: 2021 Jan 29.
DOI: 10.1038/s41467-021-20942-w
Abstrakt: 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.
Databáze: MEDLINE