Scientists discover how phosphorylation affects electron transport in mitochondria

Known as the powerhouse of cells because of their role in energy production, mitochondria are membrane-bound organelles found in nearly all eukaryotic cells (animals, plants, and fungi). Its main function in animal cells is to convert nutrients into chemical energy, stored in the form of adenosine triphosphate (ATP) molecules, through so-called cellular respiration, which includes a highly regulated process of electron transport between proteins. In addition to this function, mitochondria are also responsible for other functions, such as the induction of cell death in response to certain borderline situations in cells. Mitochondria dysfunction has been linked to a number of diseases, including dementia and heart disease.

A new study led from the Institute for Bioengineering of Catalonia (IBEC) has used cutting-edge nanoscopic techniques to gain unprecedented insight into the regulation of electron transport between proteins that drive mitochondrial processes. This research has shown that phosphorylation, the process by which a phosphate group is added and which allows adjustment of protein function, also affects electron transport in the mitochondrial respiratory chain. Due to the important role that this cell organelle plays in both health and disease states, this study is vital for understanding the function of this structure at the molecular level.

The study was carried out by Anna Lagunas (senior researcher in the IBEC Nanobioengineering group led by Josep Samitier) and Marina I. Giannotti (senior researcher in the IBEC Nanoprobes and Nanoswitches group led by Pau Gorostiza). Both are researchers at the Center for Biomedical Research in the Bioengineering, Biomaterials and Nanomedicine Network (CIBERBBN) in Spain.

The IBEC researchers Alexandre MJ Gomila, Laura Casas-Ferrer and Sthefany Ortiz-Tescari have also contributed to this study, as well as the research team led by Professor Carme Rovira from the Institute of Theoretical and Computational Chemistry of the University of Barcelona, ​​and the Professor Irene Díaz-Moreno of the Chemical Research Institute, attached to the Isla de La Cartuja Scientific Research Center, which depends on the University of Seville and the Higher Council for Scientific Research (CSIC), in Spain.

Cellular respiration is the process by which cells convert nutrients into chemical energy and release waste products. This process takes place through a set of biochemical reactions, some of which are redox reactions, which involve the transfer of electrons between proteins. In mitochondria, cytochrome c and cytochrome bc1 are two of the proteins involved in this process. A previous study carried out by Anna Lagunas and led by Pau Gorostiza from IBEC showed that these two proteins can transfer electrons over a certain distance through a charge channel established between them, which implies that the formation of a tightly bound complex in molecular recognition, thus making it possible to maintain specificity in a process that must be highly efficient. “In this new study, we wanted to better understand how phosphorylation regulates this process,” says Giannotti.

This work combines the analysis of electron transport at the molecular level with the measurement of the forces of interaction between proteins, which has allowed the research team to better understand the effects of cytochrome c phosphorylation on the molecular regulation of the mitochondrial respiratory chain. Phosphorylation has been found to alter electron transport by blocking the charging channel and increasing the affinity between cytochrome c and cytochrome c1, which would bottleneck the process by slowing down the flow of electrons in the chain. “Cytochrome c phosphorylation plays a crucial role in the regulation of mitochondrial respiration and in cellular metabolism in general,” explains Lagunas. “We observed that, due to phosphorylation, the cargo channel between cytochrome c and cytochrome c1 is disorganized and the interaction between both proteins is reinforced and moves away from the binding/disbinding equilibrium under the conditions of the experiment. This alters the diffusion pathway of cytochrome c molecules, slowing down the process and thus affecting the flow of electrons in the respiratory chain, slowing down mitochondrial respiration.”

Researchers from Marina I. Giannotti (left) and Anna Lagunas, from CIBERBBN and IBEC. (Photo: IBEC / CIBERBBN)

Although this study focused on two specific proteins, cytochrome c and cytochrome c1, the regulatory mechanism discovered could be applied to other proteins involved in electron transfer processes, as well as other biological functions and types of regulation through phosphorylation. “This is the first study to measure both the strength of the interaction and the charge transport between these two isolated proteins; By combining both measures, we have achieved a nanoscopic view of the interaction between proteins in electron transport chains and their regulatory mechanisms,” concludes Giannotti.

The study is titled “Phosphorylation disrupts long-distance electron transport in cytochrome c”. And it has been published in the academic journal Nature Communications. (Source: IBEC / CIBERBBN)