Structural biology, biochemistry and molecular simulations of mitochondrial complex I – a key role of accessory protein in biological energy conversion - Structural biology, biochemistry and molecular simulations of mitochondrial complex I – a key role of accessory protein in biological energy conversion
Structural biology, biochemistry and molecular simulations of mitochondrial complex I – a key role of accessory protein in biological energy conversion
By combining the power of structural biology, biochemistry and multiscale molecular simulations, researchers from Germany and Finland found a key role of an accessory subunit in energy production by respiratory complex I, a central bioenergetic enzyme.
Cellular respiration is a fundamental biological process in which oxygen molecule is converted into water to generate ATP – the biological currency of energy. In mitochondria of the cells, an 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 the Goethe University and the Max Planck Institute for Biophysics, Frankfurt, Germany and the Department of Physics, University of Helsinki, studied the functioning of complex I by focusing on one accessory subunit of the enzyme (NDUFA6/LYRM6).
Accessory subunits are well-known to provide a structural role, in which they stabilize assembly of large macromolecular complexes. However, surprisingly, researchers found that the highly conserved accessory subunit (NDUFA6/LYRM6) not only plays a role in structural stabilization, but is also involved in core energy conversion reactions of complex I. Molecular modeling 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 accessory subunit.
The molecular simulations were performed in the group of Vivek Sharma at the Department of Physics, University of Helsinki, who utilized the latest supercomputing infrastructure at CSC: Puhti and Mahti supercomputers. The microseconds of simulations on large-scale atomistic models of complex I (ca. 500,000 atoms) were made possible with these extensive computational resources.
In addition, simulations were also supported by PRACE infrastructure (Marenostrum and Marconi100 at BSC, Spain and CINECA, Italy, respectively).
The work highlights the strength of combining structural biology approaches with molecular simulations in explaining functioning of mitochondrial complex I, an enzyme of central importance in biological energy conversion and of biomedical relevance.
The authors are researchers at the Department of Physics, University of Helsinki.
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 11, 6008 (2020)