Lujan, Agustin LeonardoForesti, OmbrettaSugden, ConorBrouwers, NathalieFarre, Alex MateoVignoli, AlessioAzamian, MahshidTurner, AliciaWojnacki, JoséMalhotra, Vivek2023-06-162023-06-162023Lujan AL, Foresti O, Sugden C, Brouwers N, Farre AM, Vignoli A, et al. Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism. eLife. 2023 Mar 24;12:e85345. DOI: 10.7554/elife.853452050-084Xhttp://hdl.handle.net/10230/57183We 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.application/pdfeng© 2023, Lujan et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/elife.85345TANGO2Acyl-CoACell biologyHumanLipid dropletLipid peroxidationLysophosphatidic acidReactive oxygen speciesinfo:eu-repo/semantics/openAccess