1 November 2018

Recently, Alfredo Cabrera-Orefice, Ulrich Brandt and colleagues, theme Mitochondrial Diseases, concluded in Nature Communications that the movement of a critical loop of subunit ND3 located at the ubiquinone-binding pocket of respiratory complex I is required to drive proton pumping. These results corroborate one of the central predictions of their model for the mechanism of energy conversion by this mitochondrial enzyme.

Publication in Nature Communications: link.

Respiratory complex I feeds redox equivalents into oxidative phosphorylation. By linking electron transfer from NADH to ubiquinone with the translocation of protons across the inner mitochondrial membrane, it generates a major portion of the proton-motive force driving aerobic ATP synthesis, protein import and the transport of metabolites. Complex I is also a key player in signaling and pathologic mechanisms associated with reactive oxygen species (ROS) in humans. Yet, the molecular mechanism and regulation of energy conversion and ROS production by complex I remain poorly understood. However, they have hypothesized that during energy conversion by complex I, electron transfer onto ubiquinone triggers the concerted rearrangement of three protein loops of subunits ND1, ND3 and 49-kDa, thereby generating the power-stroke driving proton pumping. Their results show that fixing loop TMH1-2 of subunit ND3 to the nearby subunit PSST via a disulfide bridge introduced by site-directed mutagenesis reversibly disengages proton pumping without impairing ubiquinone reduction, inhibitor binding or the Active/Deactive transition. The X-ray structure of this variant of complex I indicates that the cross-link immobilizes but does not displace the tip of loop TMH1-2. Authors conclude that movement of this critical loop is required to drive proton pumping, which corroborates one of the central predictions of their model for the mechanism of energy conversion by complex I. Being now able to disconnect selectively and reversibly the proton pumping machinery from the redox chemistry of ubiquinone and its control by the A/D transition in itself provides an invaluable tool to finally elucidate the mechanism and regulation of mitochondrial complex I.

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