A protein implicated in a rare, genetic disorder that affects fat transport could help explain the underlying reasons behind common cardiac and muscle diseases, researchers report.
The study, in the Journal of Cell Biology, demonstrates the vital role of TANGO2 as a shuttle moving acyl-CoA within cells, and its importance in lipid metabolism and mitochondrial function. The discovery could help explain why mutations in this gene cause severe cardiomyopathies and rhabdomyolysis, particularly under energy stress conditions such as fasting, high fever, or infections.
While the genetic TANGO2 deficiency disorder is uncommon, the findings could help understand more common pathologies linked with dysfunctions in this protein.
“It could help us understand heart or muscle diseases in the general population,” explained researcher Vivek Malhotra, PhD, from the Centre for Genomic Regulation at the Barcelona Institute for Science and Technology.
“Millions of people wrestle with heart problems or abnormal fat metabolism, and the fundamental chemistry isn’t all that different. The biology of rare diseases can help us understand human health in general.”
TANGO2 mutations have been linked with neurodevelopmental delay, hypothyroidism, rhabdomyolysis, and cardiomyopathy with life-threatening arrhythmias. Patients often experience metabolic crises characterized by hypoglycemia, hyperlactatemia, and elevated long-chain acylcarnitines.
Malhotra and team investigated the role of TANGO2 further and discovered that it is localized in mitochondria, with a significant portion residing within the mitochondrial lumen. TANGO2 emerged as a potential new shuttle for intracellular trafficking acyl-CoA, binding to the latter and being involved in its metabolism. This carrier function could help explain why the loss of TANGO2 function leads to severe conditions like cardiomyopathy and rhabdomyolysis that can be linked with dysfunctions in the protein.
Its absence led to disruptions in the mitochondrial acyl-CoA pool required for lipid metabolism, especially in conditions of nutrient starvation, resulting in impaired mitochondrial function.
“It remains unclear whether TANGO2 binds acyl-CoA in the cytoplasm and transports it to the mitochondrial lumen to support the β-oxidation pathway, facilitates the presentation of acyl-CoA to specific enzymes involved in lipid metabolism, traffics to the mitochondrial lumen via the carnitine shuttle pathway, or utilizes a novel, stress-induced pathway,” the authors noted.
They added that vitamin B supplements have been reported to protect TANGO2 patients from metabolic crises and that pantothenic acid—otherwise known as vitamin B5— serves as the biological precursor for synthesizing CoA, which is essential for fatty acid metabolism in mitochondria.
“It is possible that vitamin B5 supplementation increases the production of acyl-CoA, allowing even a small pool of acyl-CoA to be transported into the mitochondria in TANGO2-deficient patients, thereby supporting the residual metabolism of essential lipids.”
