Journal: Nat Commun / Year: 2021 Title: Structural basis for a complex I mutation that blocks pathological ROS production. Authors: 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 / ...Authors: 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 / Judy Hirst / 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- ...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.
History
Deposition
Sep 29, 2020
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Header (metadata) release
Feb 3, 2021
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Map release
Feb 3, 2021
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Update
Feb 10, 2021
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Current status
Feb 10, 2021
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10605 (Title: Single particle cryo-EM dataset of Mus musculus mitochondrial complex I with ND6 P25L mutation Data size: 3.1 TB Data #1: Single particle cryo-EM dataset of Mus musculus mitochondrial complex I with ND6 P25L mutation [micrographs - multiframe])
Supramolecule #1: Mouse mitochondrial complex I with ND6-P25L mutation
Supramolecule
Name: Mouse mitochondrial complex I with ND6-P25L mutation / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#44 Details: Proline to leucine substitution at position 25 in the ND6 subunit of complex I
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