New discovery sheds light on energy crisis in children with Tango2 deficiency

New discovery sheds light on energy crisis in children with Tango2 deficiency

Researchers studying a protein linked to a rare, serious disease have made a discovery that sheds light on how cells meet their energy needs during a severe metabolic crisis. The results could lead to new treatments for the disease and open new research opportunities for other diseases involving impaired lipid metabolism.

When scientists at the Center for Genome Regulation (CRG) in Barcelona first identified a handful of protein-coding genes in 2006, they had no idea that one of them, Tango2, would eventually be linked to a life-threatening disorder in children. In 2016, researchers discovered that mutations in Tango2 cause a rare disease now officially recognized as Tango2 deficiency disorder (TDD).

There are approximately 110 known patients with TDD worldwide, although there are an estimated six to nine thousand undiagnosed patients overall.

When the body increases its energy needs, cells normally deplete their carbohydrate stores and use lipids to produce energy instead. This is particularly important for the heart, which derives between 60 and 90% of its energy needs from consuming lipids in the mitochondria of cells.

Children with Tango2 deficiency have difficulty meeting the body's energy demands, leading to life-threatening metabolic crises. These episodes are characterized by sudden drops in blood sugar, muscle breakdown (rhabdomyolysis), and potentially fatal abnormal heart rhythms (cardiac arrhythmias). The crises are often triggered by physical stress, such as: E.g. high fever, viral infections or missing a meal.

Although the rarity of TDD means most doctors will never see a case firsthand, the consequences can be devastating, and many families rely on high-quality interventions such as glucose IVs in hospitals.

“Families sometimes only find Tango2 deficiency after a dramatic incident,” says Vivek Malhotra, senior author of the study, who first discovered the Tango family of genes two decades ago. "One moment everything seems normal. Then, under a low-energy situation, these children's muscles and hearts don't keep up."

For the past decade, Malhotra's team has been studying what Tango2 does at the molecular level and why its disruption causes life-threatening symptoms. They recently showed that the protein is located in the mitochondria, suggesting that it plays an important role in energy production. They also found that Tango2-deficient cells accumulate more fat droplets and produce excess reactive oxygen species, leading to damaged or unusable lipids.

In the latest study published today in theJournal of Cell BiologyThe researchers show that Tango2 binds directly to an important fat molecule called acyl-CoA and transports it into cells like a shuttle. The study authors made the findings by labeling Tango2 with glowing markers to track their movements in living cells.

The discovery sheds new light on why metabolic emergencies occur in children with TDD. “Tango2 grabs fats and reports them for combustion.

One of the few existing treatments for the condition is to give patients high doses of vitamin B5, an essential nutrient known to produce coenzyme A.

We still don't know why vitamin B5 helps some patients avoid metabolic crises, but it may cause the residual energy pathways that Tango2 normally supports. “

Dr. Agustin Lujan, first author of the study

Although Tango2 deficiency is rare, the science of how cells switch fat to fuel-hungry tissues may be more general. “It could help us understand heart or muscle disease in the general population,” says Dr. Malhotra. "Millions of people struggle with heart problems or abnormal lipid metabolism, and the basic chemistry is not that different. The biology of rare diseases can help us understand human health in general."

The study authors now hope to determine exactly how Tango2 contracts with acyl-CoA and whether it passes these fats to specific enzymes within the mitochondria. They will also examine whether Tango2 moves between different parts of the cell during times of stress.

In practical terms, the new findings could ultimately inform treatments or at least help doctors recognize the early warning signs of Tango2 deficiency. “The more we clarify the molecular basis, the better our chances of developing targeted therapies,” says Dr. Ombretta Foresti, co-author of the study and staff scientist at the CRG. “And hopefully with better understanding, we can give families more than just emergency measures before this disease.”

The results of the study were possible thanks to an international collaboration between scientists, doctors and patient associations such as the Tango2 Research Foundation, which enabled data for analysis obtained from biological samples taken from patients with the disease.

For parents of affected children, every step forward is encouraging. “Every new discovery and insight brings us closer to where we ultimately want to be,” says Mike Morris, parent of a child with TDD and co-founder of the Tango2 Research Foundation.

“We are grateful to scientists around the world as they work to piece together this puzzle and positively impact patients and families living with TDD,” adds Kasha Morris, co-founder of the Tango2 Research Foundation.

"Over the past decade, fundamental, laboratory-based research has changed this narrative and offers hope where none once existed. This journey demonstrates the profound impact of fighting first principles in the life sciences, as well as the important collaboration between researchers, physicians and families in combating human pathologies" Conclusions Dr. Malhotra.

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