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

Zhan Yin, Nils Burger, Duvaraka Kula-Alwar, Dunja Aksentijević, Hannah R. Bridges, Hiran A. Prag, Daniel N. Grba, Carlo Viscomi, Andrew M. James, Amin Mottahedin, Thomas Krieg, Michael P. Murphy () and Judy Hirst ()
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Zhan Yin: University of Cambridge
Nils Burger: University of Cambridge
Duvaraka Kula-Alwar: University of Cambridge
Dunja Aksentijević: Queen Mary University of London
Hannah R. Bridges: University of Cambridge
Hiran A. Prag: University of Cambridge
Daniel N. Grba: University of Cambridge
Carlo Viscomi: University of Cambridge
Andrew M. James: University of Cambridge
Amin Mottahedin: University of Cambridge
Thomas Krieg: University of Cambridge
Michael P. Murphy: University of Cambridge
Judy Hirst: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-12

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.

Date: 2021
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DOI: 10.1038/s41467-021-20942-w

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