Mitochondrial complex I is a membrane complex essential for energy metabolism with a mass of almost one million Dalton. As the first component of the mitochondrial respiratory chain, it uses energy from NADH to pump protons across the inner mitochondrial membrane creating an electrical potential that then drives ATP production. Complex I is involved in the production of deleterious reactive oxygen species production and malfunctions are involved in many hereditary and degenerative disorders.
In the paper published now in SCIENCE by Uli Brandt from the Nijmegen Center of Mitochondrial Disorders (NCMD) at the Radboudumc and his collaborators, the X-ray structure of mitochondrial complex I at 3.6-3.9 Å resolution describes in detail the central subunits that execute the bioenergetic function. Featuring 84 transmembrane helices, mitochondrial complex I the largest membrane protein complex for which the structure was solved by X-ray crystallography.
A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone-binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form goes along with a concerted structural rearrangement at the ubiquinone reduction site providing support for a two-state stabilization-change mechanism of proton pumping.
The insights into the details of the structure and mechanism of this giant molecular machine will be prerequisite to understand the functional defects underlying the numerous diseases involving complex I deficiencies and this greatly help to design preventive and therapeutic strategies.
Reference in Science, 2 January 2015, Vol. 347 no. 6217 pp. 44-49
Professor Ulrich Brandt
Ulrich Brandt started his work at the NCMD in 2013. He studied chemistry and biochemistry from 1980 to 1986 at the Eberhard-Karls University in Tübingen, the Ludwig-Maximilians University in Munich and the Max Planck Institute for Biochemistry in Martinsried, Germany. In 1989 he obtained his PhD at the Ludwig-Maximilians University on the topic “Zum Mechanismus des mitochondrialen Elektronentransports - Untersuchungen mit spezifischen Hemmstoffen”. Through 1989 to 1991 he worked as a postdoctoral researcher at the Gustav-Embden Centre for Biological Chemistry at the Johann Wolfgang Goethe-University. Herafter in 1993 he worked as a researcher in biochemistry at the Dartmouth Medical School, Hanover, New Hampshire, USA. In 1994 Brandt returned to the Johann Wolfgang Goethe-University where he became a teacher in 1995 and professor in biochemistry in 1996. He recently acquired the title Adjunct Professor at the medical faculty of this insitute and of the Cluster of Excellence Frankfurt Macromolecular Complexes.