Researchers at the Weizmann Institute of Science have identified a cellular protein switch known as MTCH2, or “Mitch,” that controls whether human and animal cells burn fat or store it, offering a fundamentally new approach to obesity treatment that bypasses appetite suppression.
Inside the Mitochondrial Fragmentation Process
Scientists discovered that MTCH2 plays a vital regulatory role inside mitochondria, the cellular structures that convert food into energy-carrying adenosine triphosphate. When researchers disabled this protein in laboratory experiments, the normal structure of mitochondrial networks fragmented. Individual mitochondria became separated, shifting the balance between energy production and energy demand.
This structural disruption left human cells experiencing a persistent shortage of readily available energy relative to their needs. To compensate for the deficit, the cells significantly increased their cellular respiration, the chemical process that extracts usable energy from nutrients using oxygen. Instead of conserving energy efficiently, the altered cells began consuming higher amounts of carbohydrates, amino acids, and particularly fatty acids.
“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. The analysis revealed a direct depletion of lipid molecules in cell membranes, showing that the cells were actively breaking down their own membrane fats to use as fuel.
Halting the Adipogenesis Developmental Pipeline
Beyond increasing fat consumption, removing MTCH2 interferes with adipogenesis, the developmental process through which immature precursor cells mature into fat-storing adipocytes.
When researchers deleted MTCH2 from mouse precursor fat cells, approximately 5% to 10% of the cells successfully differentiated within six days, compared with 80% to 90% of normal precursor cells. The altered cells accumulated substantially fewer lipid droplets. Professor Atan Gross noted that the energy shortage created by disabling Mitch prevents cells from synthesizing membranes and growing, stopping the differentiation process.
Tissue-Wide Metabolic Protection and Future Trials
Earlier experiments involving mice with reduced MTCH2 activity in muscle tissue demonstrated increased metabolic activity, improved physical endurance, and protection against diet-related obesity. These findings, initially published in The EMBO Journal in January 2025, showed that the protein influences energy expenditure across tissue types.
Further research published on October 3, 2025, in Nature Communications detailed how MTCH2 regulates metabolism within fat tissue. An international team including Gross and Chourasia found that the protein physically interacts with carnitine palmitoyltransferase 1, an enzyme acting as a critical checkpoint controlling the entry of fatty acids into mitochondria.
Normally, a molecule called malonyl-CoA regulates this enzyme to limit fatty acid consumption. Removing MTCH2 altered that control system, allowing mitochondria to increase fatty acid utilization and overall energy expenditure without requiring the animals to eat less.
