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

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• dc.contributor.author Lujan, Agustin Leonardo
• dc.contributor.author Foresti, Ombretta
• dc.contributor.author Sugden, Conor
• dc.contributor.author Brouwers, Nathalie
• dc.contributor.author Farre, Alex Mateo
• dc.contributor.author Vignoli, Alessio
• dc.contributor.author Azamian, Mahshid
• dc.contributor.author Turner, Alicia
• dc.contributor.author Wojnacki, José
• dc.contributor.author Malhotra, Vivek
• dc.date.accessioned 2023-06-16T06:11:11Z
• dc.date.available 2023-06-16T06:11:11Z
• dc.date.issued 2023
• dc.description.abstract 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.
• dc.description.sponsorship We thank all members of the Malhotra laboratory for valuable discussions and critical reading of the manuscript. We thank Aida Rodriguez for advice with ROS analysis; Albert Pol and Albert Herms for advice with lipid metabolic experiments; the staff of the CRG/UPF Flow Cytometry Unit for advice with flow cytometry analysis and the staff of the CRG Advanced Light Microscopy Unit for invaluable technical help. We acknowledge the support of the Spanish Ministry of Science, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. V Malhotra is an Institució Catalana de Recerca i Estudis Avançats professor at the Centre for Genomic Regulation. V Malhotra is an Institució Catalana de Recerca i Estudis Avançats professor at the Centre for Genomic Regulation Work in the Malhotra lab is funded by grants from the Spanish Ministry of Economy and Competitiveness (Plan Nacional to VM: PID2019-105518GB-I00) and the European Research Council Synergy Grant (ERC-2020-SyG-Proposal No. 951146). AL is funded by the European Molecular Biology Organization (EMBO ALTF 659-2021), JW is funded by the European Research Council (H2020-MSCA-IF-2019-894115). OF is funded by the Ramon y Cajal program (RYC-2016-20919). This work reflects only the authors’ views, and the EU Community is not liable for any use that may be made of the information contained therein.
• dc.format.mimetype application/pdf
• dc.identifier.citation Lujan 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.85345
• dc.identifier.doi http://dx.doi.org/10.7554/elife.85345
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/57183
• dc.language.iso eng
• dc.publisher eLife
• dc.relation.ispartof eLife. 2023 Mar 24;12:e85345
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/894115
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-105518GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/951146
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword TANGO2
• dc.subject.keyword Acyl-CoA
• dc.subject.keyword Cell biology
• dc.subject.keyword Human
• dc.subject.keyword Lipid droplet
• dc.subject.keyword Lipid peroxidation
• dc.subject.keyword Lysophosphatidic acid
• dc.subject.keyword Reactive oxygen species
• dc.title Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion