Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism
- Barcelona Institute for Science and Technology, Spain
- Baylor College of Medicine, United States
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 (ROS), 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.
Data availability
"TANGO2 - Source data files" (https://doi.org/10.5061/dryad.rn8pk0pg5) to Dryad.
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TANGO2 - Source data filesDryad Digital Repository, doi:10.5061/dryad.rn8pk0pg5.
Article and author information
Author details
Agustin Leonardo Lujan
Funding
Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (PID2019-105518GB-I00)
- Agustin Leonardo Lujan
European Research Council (ERC-2020-SyG-Proposal No. 951146)
- Agustin Leonardo Lujan
- Ombretta Foresti
- Conor Sugden
- Nathalie Brouwers
- Alex Mateo Farre
- Alessio Vignoli
- Jose Wojnacki
- Vivek Malhotra
European Molecular Biology Organization (EMBO ALTF 659-2021)
- Agustin Leonardo Lujan
European Research Council (H2020-MSCA-IF-2019-894115)
- Jose Wojnacki
Ministerio de Ciencia e Innovación (RYC-2016-20919)
- Ombretta Foresti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Suzanne R Pfeffer, Stanford University, United States
Version history
- Preprint posted: November 5, 2022 (view preprint)
- Received: December 3, 2022
- Accepted: March 22, 2023
- Accepted Manuscript published: March 24, 2023 (version 1)
- Version of Record published: March 27, 2023 (version 2)
Copyright
© 2023, Lujan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism
eLife 12:e85345.
https://doi.org/10.7554/eLife.85345
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