Rare genetic disease caused by alterations to lipid metabolism

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have established a critical link between the TANGO2 gene and lipid metabolism. The study, published in the journal eLife, reveals the molecular mechanisms underlying how TANGO2 affects energy production, which explains why rare diseases caused by mutations in the gene initiates various metabolic crises, often leading to fatal outcomes.

"Mutations in TANGO2 cause a rare disease during childhood and adolescence, causing delays in neurological development,” explains Agustin Lujan, first author of the study and postdoctoral researcher in Vivek Malhotra’s lab at the Centre for Genomic Regulation in Barcelona.

“The biggest challenge are metabolic crises caused by stressful situations such as fasting, where sugar reserves are depleted and lipid reserves begin to be used for energy production instead. This can often be fatal for people living with TANGO2 mutations, and we wanted to understand the molecular mechanisms to define the function of the gene,” he adds.

Using human cell lines, the team found that products of the TANGO2 gene are predominantly localized at mitochondria - the cell's ‘battery packs’ - and also at sites where lipid droplets and the endoplasmic reticulum interact with mitochondria. Lipid droplets play a crucial role in cellular health by storing lipids for energy storage.

When TANGO2 is absent, cells exhibit enlarged lipid droplets and a significant shift in their lipid composition, indicating the gene's crucial role in maintaining lipid balance. The researchers suggest that TANGO2 function is linked to acyl-CoA metabolism, a set of chemical reactions that determines how cells process and manage fats: converting them into a form that can be used to generate energy and building blocks for other important cell components.

The lack of TANGO2 results in higher levels of reactive oxygen species, molecules which accumulate and damage cells, possibly due to compromised mitochondrial function. The researchers also observed higher levels of lipid peroxidation, a process that involves "stealing" electrons from lipids found in cell membranes, which can result in cell damage. The accumulation of peroxidised lipids and lipid metabolism explain the enlarged size of the lipid droplets observed in the study.

The research offers insights into the consequences of TANGO2 mutations, which have been known to induce severe metabolic crises such as rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to death.

The research could also explain why previous research showing that patients who consume multivitamin complexes or B-complex daily have better survival and less chance of suffering from metabolic crises. “The effect of this therapy could be due to the antioxidant activity of vitamins, which reduces levels of reactive oxygen species and/or Vitamin B molecules stimulating the formation of new lipids. Our work opens the door to improve these therapeutic strategies or create new ones that target the cellular defects observed in our experiments,” says Dr. Lujan.

Image: Cells in the laboratory with TANGO2 (left) compared to cells with TANGO2 knocked out (right). Credit: Agustin Lujan/Centre for Genomic Regulation