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Mechanistic insight from crystal structure of mitochondrial complex I

January 2015. Mitochondrial oxidative phosphorylation is the major source of cellular energy under aerobic conditions. This fundamental metabolic pathway involves five large membrane protein complexes. A team of research groups of the Frankfurt Cluster of Excellence Macromolecular Complexes (Volker Zickermann, Harald Schwalbe and Ulrich Brandt) and researchers from Freiburg University now published the 3D structure of mitochondrial complex I at 3.6 to 3.9 Å resolution in the journal Science.

The respiratory complex I generates 40% of the proton-motive force that drives ATP synthesis. ATP is the universal energy currency within the human body. The complex achieves this by an intricate coupling of a two-electron transfer reaction from NADH to ubiquinone with the translocation of four protons across bioenergetic membranes. Complex I dysfunction is implicated in a variety of neuromuscular diseases and neurodegenerative conditions.
The study by the research team led to an entirely new insight into the structural basis of redox-driven proton pumping and the reversible active-deactive transition of the enzyme complex.

Complex I from a variety of eukaryotic species adopts a deactive form under conditions that would promote excessive oxygen radical formation while the active form is induced by turnover conditions. The active-deactive transition has major implications for human health, e.g. by affecting the extent of reperfusion injury after heart surgery. The structure of mitochondrial complex I now offers clues on a conformational switch at the ubiquinone reduction site that blocks substrate access in the deactive state.

Complex I adopts an L-shaped overall architecture with a membrane arm and a peripheral arm. The long standing question concerning the catalytic mechanism of complex I is how the energy released during ubiquinone reduction in the peripheral arm is transmitted to the proton pump sites located in the membrane. Structural changes at the ubiquinone reduction site seem to be linked with rearrangement of a highly charged surface loop of a membrane bound subunit. Intriguingly, this loop is connected to a central axis of charged and polar residues running through the whole length of the membrane arm. It is now very likely that the ubiquinone reduction site adopts different conformational states during the catalytic cycle of complex I. These conformational changes are communicated to the membrane arm by inducing a propagation of charge movements and charge induced pKa changes in the hydrophilic axis that ultimately triggers proton translocation at the pump sites. More


Volker Zickermann, Structural Bioenergetics Group, Institute of Biochemistry II, Goethe University Frankfurt, Germany, Zickermann@med.uni-frankfurt.de

Harald Schwalbe, Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Germany, schwalbe@nmr.uni-frankfurt.de

Ulrich Brandt, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, The Netherlands, U.Brandt@cukz.umcn.nl


Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U (2015) Mechanistic insight from the crystal structure of mitochondrial complex I. Science 347:44-49. Link to full paper