13. Dec. 2023

Mitochondria are cellular powerhouses that produce energy for metabolic processes. Molecules called phospholipids, which are supplied to mitochondria from other parts of the cell, are important for the functioning of mitochondria. But exactly how phospholipids get into the mitochondria has long been a mystery because no dedicated transport proteins have been found in the mitochondrial membrane. However, scientists from the CEITEC research institute with colleagues from abroad have now uncovered the identity of the mystery transporter using computer simulations and described its functioning. Uncovering this transport gateway allows us to better understand how proteins work in the human body, which may be important for designing new drugs or creating proteins with new properties.

Mitochondria are organelles inside cells whose main function is to produce energy for the body. They are surrounded by two membranes that not only separate the mitochondria from the rest of the cell, but also carry out metabolic processes. These membranes are made up of phospholipids and their composition is characteristic of mitochondria. Phospholipids are produced by the endoplasmic reticulum, another specialised part of the cell whose proximity to the mitochondria allows them to communicate with each other and exchange substances. However, the supplied phospholipids have to get from the surface of the mitochondria to the inside, which is difficult for them to do, and how this happens has not yet been described.

In other parts of the cell, proteins called scramblases have been discovered that transport phospholipids across the membrane. However, no such scramblase has yet been detected in mitochondria. An international team of scientists, including biophysicists Robert Vácha and Ladislav Bartoš from CEITEC Masaryk University, has now discovered that the mitochondrial protein VDAC also functions as a scramblase. By combining different methods, the scientists have shown that lipid transport occurs when multiple VDAC proteins are attached to each other and that VDAC proteins, which are abundant in mitochondria, are the main gateway for the movement of phospholipids into the mitochondria.

"Thanks to computer simulations, we have shown that when VDAC proteins come into appropriate contact, the mitochondrial membrane thins locally, allowing phospholipids to pass from one side of the membrane to the other," explains Ladislav Bartoš, author of the simulations from Robert Vácha's research group. "In addition, the simulations allowed us to monitor the passage of individual phospholipids and quantify the whole process," adds Robert Vácha. While the previously described scramblases have a structure made up of helical segments, the VDAC protein is made up of beta-sheets folded into a barrel shape. This is the first representative of barrel-shaped scramblases, demonstrating that proteins with this transport function can have different structures.

The discovery of this principle, which was kick-started by research at Weill Cornell Medical College in the USA, may be important for further scientific investigations. Suppressing or limiting the activity of the VDAC protein may have a significant impact on processes related to metabolism and regulation of the cellular environment. In general, manipulation of protein function is essential for understanding biology and developing therapeutic and technological applications. Indeed, changes in protein function can lead to the development of drugs that target biological processes and may be key to the treatment of certain diseases or infections.

The research was published in the journal Nature Communications on December 8, 2023.

The research collaboration was funded on the part of CEITEC Masaryk University by a grant from the European Research Council (ERC) and the National Institute of Virology and Bacteriology (NIVB).