Fifty years since their discovery, scientists have finally discovered how a molecular machine that is in mitochondria, the ‘powers’ of our cells, allows us to make the fuel we need sugars, a vital process for a lifetime on earth.
The scientists of the Mitochondrial Biology Unit of the Medical Research Council (MRC), University of Cambridge, have resolved the structure of this machine and have demonstrated how it operates as the blockade in a channel to transport pyruvate, a molecule generated in the body from the decomposition of sugars, to our mitochondria.
Known as mitochondrial pyruvate bearer, it was proposed that this molecular machine exist for the first time in 1971, but until now it has taken scientists to visualize its structure at an atomic scale using cryo -electronic microscopy, a technique used to magnify an image of an object to around 165,000 times its real size. Details are published today in Scientific advances.
Dr. Sotiria Tavouulari, an associated main investigation of the University of Cambridge, who first determined the composition of this molecular machine,: “The sugars in our diet provide energy so that our bodies work. When they are broken down into our cells, they produce pyruvate, but so that more outside this molecule should be transferred within the powers of the cells, the mitocond. ATP “.
Maximilian Sichrovsky, a doctoral student at Hughes Hall and the first author of the study, said: “Bring our mitochondria to pyruvate sounds simple, but so far we have not been able to understand the mechanism of how this process occurs. Using the use of the crio-electrons of art of art, and we will take into account that we have not only been able to have this transporter, but it is exactly the way it is exact It is exactly how it works, and it is exactly how it works.
Mitochondria are surrounded by two membranes. The exterior is porous, and the pyruvate can easily pass, but the internal membrane is impervious to pyruvate. To transport pyruvate to the mitochondria, first an external ‘door’ door is opened, allowing the pyruvate to enter the bearer. This door closes, and the internal door opens, which allows the molecule to pass to the mitochondria.
“It works like locks in a channel but on the molecular scale,” said Professor Edmund Kunji of the MRC Mitochondrial Biology Unit, and a trinity hall member, Cambridge. “There, a door opens at one end, allowing the boat to between. Then it closes and the door at the opposite end opens to allow the boat to be soft in transit.”
Due to its central role in the control of the way in which the mitochondria operates to produce energy, this bearer is now recognized as a promising drug target for a variety of conditions, including diabetes, fatty liver disease, Parkinson’s disease, specific cancers and even hair loss.
Pyruvato is not the only energy source available to us. Our cells can also take their energy from the fats stored in the body or amino acids in protein. Blocking the pyruvate bearer would force the body to look elsewhere, creating opportunities to treat a series of diseases. In fatty liver disease, for example, blocking access to pyruvate entry into mitochondria could encourage the body to use potentially dangerous fat that has been stored in liver cells.
Similarly, there are certain tumor cells that depend on pyruvate metabolism, as in some types of prostate cancer. These cancers tend to be very “hungry”, producing an excess of pyruvate transport carriers to ensure that they can feed more. Block the bearer could starve these cancer cells of the energy they need to survive, killing them.
Previous studies have also suggested that inhibiting mitochondrial pyruvate bearer can reverse hair loss. The activation of human follicle cells, which are responsible for hair growth, is based on metabolism and, in particular, lactate generation. When the mitochondrial pyruvate bearer is blocked to enter mitochondria in these cells, instead it becomes lactate.
Professor Kunji said: “Drugs that inhibit the carrier function can remodel how mitochondria works, which can be beneficial in certain conditions. Electronic microscopy allows us Real game change.
The research was supported by the Medical Research Council and was a collaboration with the Vanessa Leone groups at the Medical College of Wisconsin, Lucy Forrest in the National Health and Jan Steyert Institutes at the Free University of Brussels.