Researchers at Tel Aviv University have made a major breakthrough in understanding a rare neurological disease that causes epilepsy, developmental delays, and intellectual disabilities. Their work could pave the way for new treatments for this condition and similar disorders linked to energy production issues in cells.
The team, led by Tel Aviv University’s Prof. Abdussalam Azem and Prof. Uri Ashery, developed a unique research model using mouse brain cells to study the disease. They found that the problem stems from a mutation in a protein called TIMM50, which is critical for transporting other proteins into mitochondria – the “powerhouses” of cells. This mutation disrupts energy production and causes abnormal electrical signals in the brain, contributing to the disease’s symptoms. Importantly, the study identified damaged potassium channel proteins as a potential target for future treatments.
By decoding the disease mechanism and creating a new research model, the scientists have opened doors for further research and development of therapies that could transform patients’ lives. Prof. Uri Ashery shared the details of this groundbreaking study with The Media Line.
One of the most important organelles in a cell is the mitochondria, often called the ‘powerhouse’ of the cell because it provides energy for the whole body. In this study, we focused on a mutation in the TIMM50 protein, which is crucial for importing about 1,500 proteins into the mitochondria. Without this process, the mitochondria can’t function properly, leading to severe consequences.
“One of the most important organelles in a cell is the mitochondria, often called the ‘powerhouse’ of the cell because it provides energy for the whole body,” Ashery explained. “In this study, we focused on a mutation in the TIMM50 protein, which is crucial for importing about 1,500 proteins into the mitochondria. Without this process, the mitochondria can’t function properly, leading to severe consequences.”
Dr. Shahar Shelly, Head of Neurology at Rambam Health Care Campus, underscored the central role of mitochondria in cellular function and its relevance to a wide range of diseases. “Mitochondria produce energy and maintain cellular homeostasis. Any time there is a pathological process or disease, mitochondria are affected,” Shelly told The Media Line.
True mitochondrial diseases, where the primary issue is in the mitochondria itself, are extremely rare—around one in two million. However, mitochondrial dysfunction as part of broader metabolic or oxidative abnormalities is incredibly common, even beyond neurology.
“True mitochondrial diseases, where the primary issue is in the mitochondria itself, are extremely rare—around one in two million. However, mitochondrial dysfunction as part of broader metabolic or oxidative abnormalities is incredibly common, even beyond neurology,” he added.
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Shelly cautioned against oversimplifying the role of mitochondria in disease. “Many patients think mitochondrial dysfunction is the key to their solution, but in most cases, it’s an epiphenomenon—a byproduct of the disease rather than the root cause,” he explained. “It’s like going to a supermarket: no matter what you buy—milk, vegetables, or cereal—you always go to the same cashier to pay with your credit card. Mitochondria are like that cashier, a common pathway for various cellular problems.”
The study took a new approach, moving beyond traditional research that examined the mutation in non-neuronal cells. “Previous studies analyzed the mutation in general cells, like skin cells, but didn’t link it to the brain, where the disease actually manifests,” Ashery said.
“This is why we decided to bridge this gap. We combined the expertise of my lab, which focuses on neuronal function, with Prof. Azem’s lab, which specializes in mitochondria and their related proteins,” Ashery added.
To begin, the researchers worked with a family in Israel where two siblings had the mutation while the father was healthy. “We collected skin cells from the siblings and their father and studied the mutation in those fibroblasts. We found a dramatic reduction in the expression of TIMM50, which severely affected the mitochondria’s ability to breathe and produce ATP—essential for energy,” Ashery shared.
The team then developed a model using neurons from mouse brains. “We reduced TIMM50 levels in these neurons by 80%, simulating the mutation’s effects. This was the first time anyone studied the impact of this mutation in brain cells, where the disease actually occurs,” Ashery explained.
We found several important results. First, the mitochondria’s ability to produce ATP was significantly reduced. Second, the transport of mitochondria along the neuron was impaired—it moved slower and stopped frequently. This is critical because neurons are very long, sometimes up to a meter in humans, and rely on mitochondria for energy transport.
“We found several important results. First, the mitochondria’s ability to produce ATP was significantly reduced. Second, the transport of mitochondria along the neuron was impaired—it moved slower and stopped frequently. This is critical because neurons are very long, sometimes up to a meter in humans, and rely on mitochondria for energy transport.”
According to Ashery, a surprising discovery emerged when the researchers analyzed potassium channels in the neurons. “We found a reduction in the expression of two proteins critical for potassium channel function. These channels are essential for transmitting electrical signals in the brain,” he said. “This reduction led to increased firing rates of action potentials, which correlates with the epileptic activity seen in patients.”
Discussing future applications, Ashery shared the team’s next steps: “We are now differentiating the patient-derived skin cells into cortical neurons in a specialized lab. If we observe the same phenomena—reduced TIMM50 levels, impaired energy production, and increased firing rates—it will confirm the mutation’s direct effects in patient-derived neurons. This will allow us to test anti-epileptic drugs on these neurons, which could significantly shorten the path to clinical trials.”
While optimistic about these prospects, he noted the time and effort required: “The current study took four to five years. Creating cortical neurons and testing drugs will likely take another four to five years. After that, we could potentially move to clinical trials if we find effective treatments in the lab. While the timeline is still long, understanding the disease mechanism for the first time gives us a strong foundation.”
Shelly confirmed that “a molecular marker penetrating real-world clinical practice typically takes around five to ten years if the findings are validated. It needs to show efficacy, gain regulatory approval, and work in practical settings—not just specialized labs.”
Ashery also highlighted challenges in the research process. “Funding is a major obstacle, especially for rare diseases like this, which pharmaceutical companies often overlook. Fortunately, the Israel Science Foundation supported our work. Another limitation is the rarity of the disease, making it difficult to access patient samples for further study.”
When discussing the severity of mitochondrial disorders, Shelly explained: “Mortality and morbidity vary widely depending on the type and onset of the condition. For instance, infantile-onset forms like Leigh syndrome have higher mortality rates. Childhood-onset conditions like MELAS—mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes—can range from severe to milder cases. Adults with conditions like MERRF [myoclonic epilepsy with ragged red fibers] tend to face long-term complications rather than immediate mortality.”
Despite the lack of cures, management strategies focus on improving quality of life. “There is no cure for mitochondrial diseases today,” Shelly stated. “Management involves a holistic approach with a multidisciplinary team, including neurologists, physiotherapists, psychologists, and specialists from fields like gastroenterology and orthopedics. Dietary supplements can also play a role, but the main goal is rehabilitation and helping patients live with the condition.”
Mitochondrial dysfunction is common in many neurological disorders. This research provides a new platform to study other mutations in mitochondrial proteins and explore targeted treatments. We are now in a position to approach pharmaceutical companies to develop drugs based on our findings, and I’m optimistic about the path forward.
Ashery emphasized the study’s broader implications: “Mitochondrial dysfunction is common in many neurological disorders. This research provides a new platform to study other mutations in mitochondrial proteins and explore targeted treatments. We are now in a position to approach pharmaceutical companies to develop drugs based on our findings, and I’m optimistic about the path forward.”
Regarding the potential impact of studies like the TIMM50 research, Shelly expressed cautious optimism. “Understanding the mitochondrial dysfunction in diseases like these is the first step toward targeted treatments, though significant hurdles remain before implementation in clinical practice,” he concluded.