Researchers from the Hebrew University have identified a neural network that works against the feeling of reward – and offer a new therapeutic approach to dealing with drug addiction by regulating emotional pain during withdrawal.
Prof. Rachel Nechushtai from the Hebrew University is researching MiNT (CISD3) – a protein that has not been studied in depth so far – and is discovering its critical role in maintaining mitochondrial integrity, skeletal and cardiac muscle health, and protection against oxidative damage.
Thousands of coordinated systems operate in the cells of our bodies that produce energy, build tissues, and maintain a delicate metabolic balance. One of the most important of these is a protein system containing iron-sulfur clusters ([2Fe-2S]), located in the mitochondria – the powerhouse of the cell. This system has been studied for the past decade by Prof. Rachel Nechushtai of the Hebrew University, focusing on a particularly mysterious protein: MiNT, or by its genetic name CISD3.
This protein, which belongs to the NEET protein family, was until recently virtually unknown. While its family members – CISD1 and CISD2 – have already been linked to diseases such as diabetes, hereditary neurological diseases and even cancer, CISD3 has not yet been assigned any clear role. “For years, no one knew what it did,” says Nechushtai. “But precisely because of that – we felt we had to understand.”
Her lab created a genetically engineered mouse model lacking the MiNT protein. And before long, it turned out to be a crucial protein: The mice began to lose their ability to move, suffered from muscle atrophy, and showed symptoms reminiscent of a very well-known disease—Duchenne muscular dystrophy (DMD). “It wasn’t just one isolated defect—it was a total collapse of mitochondrial function in skeletal and cardiac muscle,” she explains.
Microscopic examinations revealed severe damage to the structure of the mitochondria, including the disappearance of the inner membrane. Functional measurements revealed a sharp decrease in the ability to produce energy (ATP) through the cellular respiration (OXPHOS) pathway, while the glycolysis pathway – which occurs outside the mitochondria – was preserved. “This was a clear indication that the problem was centered in the mitochondria themselves,” says Prof. Nehushtai.
But the real innovation in the study is not just in characterizing the defect, but in understanding MiNT’s unique role as a “chaperone” – a “chaperone” molecule that transports iron-sulfur clusters within the cell. These clusters are required for the function of many enzymes, and especially for the balance of iron, calcium and free radicals. “We think that MiNT is the central player that transports the iron-sulfur cluster from the mitochondrial matrix to the cytosol, and maintains the overall integrity of the cell,” she emphasizes.
A broad proteomic profile of the mice’s muscles showed a 30% decrease in mitochondrial protein expression. The researchers compared these patterns to known damage from other diseases that affect muscle, such as Parkinson’s, Alzheimer’s, multiple sclerosis, and Huntington’s, and found significant overlap. “We found damage similar to what is seen in aging and degenerative diseases,” notes Nechushtai. “In other words, this protein is not only important—it probably protects against the breakdown of entire systems in the body.”
The research project is supported by the National Science Foundation, and is based on a collaboration with Prof. Ron Mittler from the University of Missouri, with whom the mouse model was developed by postdoctoral fellow Dr. Ala Carmi. The researcher plans to expand the experiments to cardiac cells and blood vessel tissues, assuming that the MiNT protein is essential not only for muscle – but also for maintaining the integrity of blood vessels, preventing atherosclerosis and other damage related to free radicals.
Furthermore, her research group is investigating ways to restore the protein’s function using modified mutants or small molecules that can mimic its activity. “If we can develop a way to stimulate the protein or replace it in damaged cells, that could be the basis for treating degenerative diseases of the muscle, heart, and perhaps even the brain and heart,” she says cautiously.
Prof. Nehushtai is now considered one of the world’s leading researchers on NEET proteins. “For me,” she concludes, “this research is not just about a protein – it’s about a deep understanding of what makes the body function, and what goes wrong when it’s damaged and/or gone. And such an understanding is the basis for any future medical breakthrough.”
Although she is currently identified with research in molecular biology and cell biochemistry, Prof. Rachel Nechushtai's scientific path began in the field of biophysics. She conducted her first research in the field of photosynthesis in plants, out of a deep interest in energy and light absorption mechanisms. Over the years, and after participating in prominent studies at universities in the US, she decided to move on to studying cells in animals – a step that she says was natural: “At a certain point, I felt that the real challenge was to understand how it works in our bodies – not just in plants. There is a lot of knowledge about the function of iron-sulfur proteins in plants, but in animals in mitochondria, I had a feeling that we could decipher new processes. In general, human biology is like a vast network of processes that we have not yet deciphered.”
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