Cellular respiration is a fundamental biological process in which an oxygen molecule is converted into water to generate ATP (adenosine triphosphate) – the biological currency of energy. In the mitochondria of the cells, electrical circuitry carries out complicated oxidation-reduction reactions, which eventually leads to the generation of ATP. The first component of this biological battery is mitochondrial complex I, a very large 1-mega-Dalton protein. Point mutations in this enzyme are known to be associated with several neurodegenerative and mitochondrial disorders.
In this study, researchers from Goethe University and the Max Planck Institute for Biophysics, Frankfurt, Germany, and the Department of Physics, University of Helsinki (UH), Finland studied the functioning of complex I by focusing on one accessory subunit of the enzyme (NDUFA6/LYRM6). Accessory subunits are known to provide a structural role, in which they stabilise the assembly of large macromolecular complexes.
Surprisingly, the researchers found that the highly conserved accessory subunit (NDUFA6/LYRM6) not only plays a role in structural stabilisation, but is also involved in core energy conversion reactions of complex I. Molecular modelling and multiscale simulations identified a putative proton transfer pathway through which protons required for substrate reduction can be transferred, but it was found to be blocked due to structural perturbations induced by point mutations in the accessory subunit.
The molecular simulations were performed in the group under Vivek Sharma at the Department of Physics, University of Helsinki. The group utilised the latest supercomputing infrastructure at CSC – IT Center for Science Ltd, Finland, the supercomputers Puhti and Mahti. The microseconds of simulations on large-scale atomistic models of complex I (approx. 500,000 atoms) were made possible with these extensive computational resources. In addition, the simulations were also supported by PRACE infrastructure (Marenostrum at BSC, Spain and Marconi100 at CINECA, Italy).
The work highlights the strength of combining structural biology approaches with molecular simulations in explaining the functioning of mitochondrial complex I, an enzyme of central importance in biological energy conversion and of biomedical relevance.
Etienne Galemou Yoga, Kristian Parey, Amina Djurabekova, Outi Haapanen, Karin Siegmund, Klaus Zwicker, Vivek Sharma, Volker Zickermann & Heike Angerer. Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I. Nature Communications, 26 November 2020
Academy research fellow Vivek Sharma, firstname.lastname@example.org