National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM137929
United States
Citation
Journal: Elife / Year: 2023 Title: Resting mitochondrial complex I from adopts a helix-locked state. Authors: Abhilash Padavannil / Anjaneyulu Murari / Shauna-Kay Rhooms / Edward Owusu-Ansah / James A Letts / Abstract: Respiratory complex I is a proton-pumping oxidoreductase key to bioenergetic metabolism. Biochemical studies have found a divide in the behavior of complex I in metazoans that aligns with the ...Respiratory complex I is a proton-pumping oxidoreductase key to bioenergetic metabolism. Biochemical studies have found a divide in the behavior of complex I in metazoans that aligns with the evolutionary split between Protostomia and Deuterostomia. Complex I from Deuterostomia including mammals can adopt a biochemically defined off-pathway 'deactive' state, whereas complex I from Protostomia cannot. The presence of off-pathway states complicates the interpretation of structural results and has led to considerable mechanistic debate. Here, we report the structure of mitochondrial complex I from the thoracic muscles of the model protostome . We show that although complex I (-CI) does not have a NEM-sensitive deactive state, it does show slow activation kinetics indicative of an off-pathway resting state. The resting-state structure of -CI from the thoracic muscle reveals multiple conformations. We identify a helix-locked state in which an N-terminal α-helix on the NDUFS4 subunit wedges between the peripheral and membrane arms. Comparison of the -CI structure and conformational states to those observed in bacteria, yeast, and mammals provides insight into the roles of subunits across organisms, explains why the -CI off-pathway resting state is NEM insensitive, and raises questions regarding current mechanistic models of complex I turnover.
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