Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism

• DOI: 10.7554/elife.85345
• Publication Date: 2023-03-24T13:01:23Z
• Authors: Agustin Leonardo ...; Ombretta Foresti; Conor Sugden; Nathalie Brouwers; Alex Mateo Farre; Alessio Vignoli; Mahshid Azamian; Alicia Turner; Jose Wojnacki; Vivek Malhotra
• Keywords: Lipid droplet; Lipotoxicity; Catabolism; Bioenergetics; Homeostasis

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