We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen species, and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.

High fructose intake induces an insulin resistance state associated with metabolic syndrome (MS). The effect of vascular inflammation in this model is not completely addressed. The aim of this study was to evaluate vascular remodeling, inflammatory and oxidative stress markers, and atheroma development in high-fructose diet-induced insulin resistance of ApoE-deficient mice (ApoE-KO). Mice were fed with either a normal chow or a 10% w/v fructose (HF) in drinking water over a period of 8 weeks. Thereafter, plasma metabolic parameters, vascular remodeling, atheroma lesion size, inflammatory markers, and NAD(P)H oxidase activity in the arteries were determined. HF diet induced a marked increase in plasma glucose, insulin, and triglycerides in ApoE-KO mice, provoked vascular remodeling, enhanced expression of vascular cell-adhesion molecule-1 (VCAM-1) and matrix metalloprotease 9 (MMP-9) and enlarged atherosclerotic lesion in aortic and carotid arteries. NAD(P)H oxidase activity was enhanced by fructose intake, and this effect was attenuated by tempol, a superoxide dismutase mimetic, and losartan, an Angiotensin II receptor antagonist. Our study results show that high-fructose-induced insulin resistance promotes a proinflammatory and prooxidant state which accelerates atherosclerotic plaque formation in ApoE-KO mice.

Loss of TANGO2 in humans precipitates metabolic crises during periods of heightened energy demand, such as fasting, infections, or high fever. TANGO2 has been implicated in various functions, including lipid metabolism and heme transport, and its cellular localization remains uncertain. In our study, we demonstrate that TANGO2 localizes to the mitochondrial lumen via a structural region containing LIL residues. Mutations in these LIL residues cause TANGO2 to relocate to the periphery of lipid droplets. We further show that purified TANGO2 binds acyl-coenzyme A, and mutations in the highly conserved NRDE sequence of TANGO2 inhibit this binding. Collectively, our findings suggest that TANGO2 serves as an acyl-coenzyme A binding protein. These insights may provide new avenues for addressing the severe cardiomyopathies and rhabdomyolysis associated with defective TANGO2 in humans.

We show that TANGO2, which lacks a transmembrane domain localizes predominantly to mitochondria and transiently to endoplasmic reticulum (ER) and lipid droplets (LDs). Evaluation of lipids in HepG2 cells lacking TANGO2 revealed an increase in the size of lipid droplets and reactive oxygen species production. There is also a marked increase lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes are exacerbated in nutrient starved cells. Based on our data, we suggest that the principle function of TANGO2 is in acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. This defect subsequently affects metabolism of many other fatty acids. These data help explain the physiological consequence of TANGO2 that induce acute metabolic crisis including rhabdomyolysis, cardiomyopathy and cardiac arrhythmias often leading to fatality upon starvation and stress.

Brugada syndrome (BrS), traditionally associated with ventricular arrhythmic risk, may also involve conduction disturbances. SCN5A deleterious variants predispose to bradyarrhythmias and atrioventricular block, posing the challenge of pacemaker implantation in young patients. A 17-year-old girl with BrS and SCN5A p.(Glu901Lys) pathogenic variant presented with recurrent presyncope, dyspnea, and more than 3,000 second-degree atrioventricular blocks documented on 24-hour Holter monitoring. Atropine administration reversed the block, confirming a functional origin. Biatrial approach cardioneuroablation (CNA) guided by electroanatomical mapping without fluoroscopy restored normal conduction and improved sinus rate. After 12 months, the patient remained asymptomatic and free of bradyarrhythmias. CNA restores autonomic balance and corrects functional bradyarrhythmias in BrS, avoiding permanent pacing. Success of CAN depends on accurate identification of the functional mechanism and expertise in autonomic mapping. In BrS, vagally mediated functional bradyarrhythmias may respond to atropine testing. CNA offers a physiological and durable alternative to pacemaker implantation in young patients with functional atrioventricular block.