Scientists at the Weizmann Institute of Science have identified a protein called MTCH2, nicknamed “Mitch,” that appears to play a major role in how cells manage energy and store fat. In a recent study published in the EMBO Journal, the team found that disabling this protein in human cells increases the rate at which fats and carbohydrates are burned while also reducing the formation of new fat cells.

The findings build on earlier research in mice that produced a surprising result. Animals lacking Mitch in their muscles became more physically fit, developed greater endurance, and were remarkably resistant to obesity.

A Surprising Discovery in Mice

Several years ago, Prof. Atan Gross and his colleagues made an unexpected observation while studying Mitch. When the researchers suppressed production of the protein in mouse muscle tissue, the animals showed major improvements in body composition.

The mice not only avoided obesity but also developed more muscle fibers. These fibers consume large amounts of oxygen and are associated with improved stamina and athletic performance. The animals performed better during physical stress tests and showed improved heart function as well.

The discovery raised an important question. How could disabling a single protein both protect against obesity and enhance physical endurance?

To answer that question, researchers turned their attention to mitochondria, the tiny structures inside cells often described as their power plants. Mitochondria generate the energy that cells need to function and play a central role in metabolism, the collection of chemical processes that convert food into usable energy.

How Mitochondria Influence Fat Burning

The shape and organization of mitochondria can reveal a great deal about how cells produce energy.

Sometimes mitochondria fuse together into large interconnected networks that generate energy efficiently. In other situations, they remain separated into smaller individual units that are less efficient. When energy production becomes less efficient, cells compensate by consuming larger amounts of fuel, including fats, carbohydrates, and proteins.

Over years of research, Gross’s team in Weizmann’s Immunology and Regenerative Biology Department discovered that Mitch helps control this process by regulating mitochondrial fusion. This finding offered a possible explanation for the unusual results seen in mice.

The next step was determining whether the same mechanism operates in human cells.

What Happens When Mitch Is Removed?

The new study, led by doctoral student Sabita Chourasia, used genetic engineering techniques to eliminate the Mitch protein from human cells.

The results were dramatic.

Without Mitch, the normal mitochondrial network broke apart into separate units. Energy production became less efficient, leaving cells in what researchers describe as a constant state of energy shortage.

At first glance, that might seem harmful. However, when the goal is to increase energy expenditure and reduce fat accumulation, this type of inefficiency can actually work in the body’s favor. Cells that struggle to produce energy must consume more fuel to meet their needs.

“After deleting Mitch, we examined, every few hours, the effect that had on more than 100 substances taking part in metabolism in human cells,” Chourasia explains. “We saw an increase in cellular respiration, the process in which the cell produces energy from nutrients, such as carbohydrates and fats, using oxygen. This explains the increase in muscular endurance in previous experiments using mice.”

Human Cells Begin Consuming More Fat

Because the altered cells required more energy, they increased their consumption of available fuel sources.

Researchers observed greater breakdown of fats, carbohydrates, and amino acids. They also found a significant shift in how cells generated energy.

Ordinary cells typically rely more heavily on carbohydrates and proteins. Cells lacking Mitch, however, depended much more on fat as their primary fuel source.

“We discovered that deleting Mitch led to a major drop in fats in membranes,” Gross explains. “At the same time, we saw an increase in fatty substances used to produce energy, and we realized that the fat was being broken down from the membrane to be used as fuel. In other words, we showed that Mitch determines the fate of fat in human cells.”

The findings suggest that Mitch acts as an important regulator that helps decide whether fat is stored or burned.

Blocking the Formation of New Fat Cells

The researchers discovered another important effect of removing Mitch.

Previous studies had shown that women with obesity tend to have elevated levels of the protein. That observation led the team to investigate whether Mitch might also influence the creation of new fat cells.

Fat cells originate from precursor cells known as progenitor cells. Under the right conditions, these immature cells accumulate fat and develop into mature fat-storing cells through a process called differentiation.

When the researchers removed Mitch from progenitor cells, that transformation became much more difficult.

“When we deleted Mitch from the progenitor cells, we discovered that the environment created in these cells was not conducive to the synthesis of new fats,” Gross explains. “Reducing the ability to synthesize membranes prevents the cells from growing, developing and reaching the point where differentiation is possible. The process of fat accumulation requires a large amount of available energy, but in cells without Mitch, there is a shortage of energy. In addition, the expression of genes necessary for differentiation is suppressed, and there is a shortage of the substances vital for this process to occur. As a result, differentiation of new fat cells is reduced, along with fat accumulation.”

In other words, cells lacking Mitch not only burned more fat but were also less capable of creating new fat-storing cells.

A Potential New Direction for Obesity Research

Although the work was conducted in cells and is still far from becoming a treatment, the findings reveal a powerful biological pathway that influences both energy use and fat storage.

By increasing fat burning while simultaneously limiting the formation of new fat cells, targeting Mitch could eventually provide researchers with a new strategy for combating obesity. The discovery may also help address one of the most persistent challenges associated with modern weight loss therapies: preserving healthy muscle while reducing excess body fat.

The study involved researchers from the Weizmann Institute of Science, the University of Pennsylvania, and the University of Texas at San Antonio.

Prof. Atan Gross holds the Marketa & Frederick Alexander Professorial Chair. His research is also supported by Amnon Shoham.