Mitch blocking, a protein that regulates energy control, prevents fats from accumulating in human cells.
About ten years ago, a new generation of weight loss drugs promised a thinner and healthy future. But there was a problem: although these drugs helped lose fat, they also led to a loss of muscle mass.
Now scientists can be on the verge of a breakthrough. In a fortuitous discovery, Professor Atan Gross of the Weizmann Institute of Sciences and his team identified a protein in muscle cells called MTCH2, or “Mitch” for short, which plays a key role in metabolism. When they turned off the Mitch gene in mouse, something incredible happened. Animals have not only become obesity resistant, but their endurance has skyrocketed, all thanks to a significant boost of metabolic activity.
Based on this success, the Gross team recently pushed research later. In a new study published in The Journal EmboThey found that mitch deactivation in human cells also accelerates fat and carbohydrate burn. Even more exciting, he prevented new fatty cells from being completely formed.
Back in mouse studies, the results were just as impressive. The mice did not just avoided gain weight. They have in fact developed more muscle fibers, which are known to consume a lot of oxygen and improve endurance.
These welcome changes have led to an improvement in the performance of stress tests and cardiac function, but have left researchers confronted with a mystery: how to silence the expression of a single protein “inoculates” the body against obesity and, at the same time, improves muscle endurance? The search for a response led them to power plants in the cell, the tiny organelles of the mitochondria responsible for the production of energy and the conduct of cell metabolism.
The role of mitochondria in metabolism
We can learn a lot about mitochondria simply by observing their shape and distribution in the cell. These organelles can merge, forming a large network of power plants which are very effective energy producers, or they can exist as separate organites which are less effective in generating energy. To overcome the decrease in efficiency, these separate organelles must use a variety of energy resources – such as fats, carbohydrates and proteins – at a higher rate.
Over the years, the Gross team in the Department of Biology of Immunology and the Regeneration of Weizmann has discovered that in addition to regulating metabolism, Mitch is one of the main regulators governing mitochondrial fusion, which helps us to understand the results in mice. But would Mitch silence have similar results in humans?
In the new study, researchers, led by doctoral students Sabita Chourasia, examined what happens to human cells when the Mitch protein is removed using genetic engineering. Scientists have found that the mitochondrial network is collapsing, the organelles separate, the effectiveness of energy production decreases – and the cell goes to a permanent state of energy deprivation. This may resemble a nightmare scenario, but sometimes the lack of energy and its ineffective production can be beneficial – because, for example, when the objective is to compensate for the overeating or to stimulate the use of fat deposits and prevent the accumulation of fat.
“After deleting Mitch, we examined every few hours, the effect that had more than 100 substances participating in metabolism in human cells,” explains Chourasia. “We have seen an increase in cellular breathing, the process in which the cell produces energy from nutrients, such as carbohydrates and fats, using oxygen. This explains the increase in muscle endurance in previous experiences using mice. ”
Burning fat, not just calories
To increase the rate of their breathing, cells need more nutrients, which serve as fuel in the energy production process. The researchers saw that the high demand for fuel had caused human cells from which they had suppressed Mitch to “burn” more substances such as fats, carbohydrates and carbohydrates
“Data-gt-translate-attributes =” ({“attribute =” “tabindex =” 0 “role =” link “> AMINO ACIDES. In addition, while regular cells use more carbohydrates and protein, rather than fat, to produce energy, Mich cells count largely on fat to produce energy and develop. “We discovered that Mitch’s abolition has led to a major drop in fats in the membranes,” explains Gross. “At the same time, we have seen an increase in the fatty substances used to produce energy, and we realized that fat was broken down from the membrane to be used as fuel. In other words, we have shown that Mitch determines the fate of fat in human cells. ”
During the next stage of the study, the researchers discovered that the involvement of Mitch in the accumulation of fat in the body goes even further. As we knew that women with obesity have high levels of Mitch, researchers have applied that this protein is vital not only for mitochondrial fusion but also for the differentiation of oily cells, in which progenituric cells accumulate fat and turn into mature fat cells.
“When we removed Mitch from the progenitor cells, we discovered that the environment created in these cells was not conducive to the synthesis of new fats,” explains Gross. “Reducing the ability to synthesize membranes prevents cells from developing, developing and reaching the point where differentiation is possible. The fat accumulation process requires a large amount of energy available, but in Mich -free cells, there is an energy shortage. accumulation. “”
In light of these promising results, the Gross laboratory is currently working, in collaboration with Bina – the Translational Research Unit of the Weizmann Institute which identifies projects at an early stage with an application potential – on a full program to develop a new small molecule which inhibits Mitch and can serve as an effective treatment for obesity. The program is carried out in partnership with Yeda Research and Development Company, the Weizmann technology transfer branch.
Reference: “MTCH2 controls energy demand and expenses to fuel anabolism during adipogenesis” of Sabita Chourasia, Christopher Putucci, Clarissa Shoffler, Dina Abbasian, Hu Wang, Xianlin Han, Ehud Sivan, Alexander Brandis, Tevie Mehlman, Sergey Malatsk Dassa, Limor Regev, Yehudit Zaltsman and Atan Gross, January 3, 2025, The Journal Embo.
DOI: 10.1038 / S44318-024-00335-7
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