Institut de Biologie StructuraleGrenoble / France

Towards the mechanism of action of the mitochondrial Complex I assembly complex

The respiratory complexes located in the inner membranes of our mitochondria are true macromolecular batteries : they couple the flow of electrons through a wire of metal clusters and co-factors with proton transfer to create a gradient that provides the energy needed to produce ATP and thus power the essential processes of life. The first complex in the respiratory chain, called Complex I, is one of the largest membrane proteins, composed of 45 subunits. The processes involved in assembly of Complex I and its sophisticated regulation are still poorly understood, but it is known that their disruption leads to neurogenerative diseases such as Alzheimer’s and accompanies the ageing process in general. In this manuscript, resulting from a collaboration between the Montserrat Soler-Lopez team at ESRF and researchers at IBS, a combination of biochemical, biophysical and structural techniques was used to elucidate the mechanism of action of a sub-complex of the human Complex I assembly complex. The ECSIT protein was found to play a key role in the regulation of the ACAD9 protein which switches between two incompatible activities. Indeed, the binding of ECSIT to ACAD9 ejects the FAD cofactor necessary for the involvement of ACAD9 in fatty acid oxidation, in order to redirect it towards action in Complex I assembly. These results are of great relevance to the field of mitochondrial neurobiology, and open multiple research avenues.

Assembly of the mitochondrial Complex I assembly complex suggests a regulatory role for deflavination. Giachin G, Jessop M, Bouverot R, Acajjaoui S, Saidi M, Chretien A, Bacia-Verloop M, Signor L, Mas PJ, Favier A, Borel Meneroud E, Hons M, Hart DJ, Kandiah E, Boeri Erba E, Buisson A, Leonard G, Gutsche I and Soler-Lopez M. Angewandte chemie 2020 ; doi : 10.1002/anie.202011548

Contact : Irina Gutsche (Microscopic Imaging of Complex Assemblies Group)