Publication Date
3-24-2023
Journal
eLife
DOI
10.7554/eLife.85345
PMID
36961129
PMCID
PMC10042531
PubMedCentral® Posted Date
3-24-2023
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Animals, Humans, Endoplasmic Reticulum, Fatty Acids, Fibroblasts, Homeostasis, Lipid Droplets, Lipid Metabolism, Mammals, Mitochondrial Proteins, Vesicular Transport Proteins
Published Open-Access
yes
Recommended Citation
Lujan, Agustin Leonardo; Foresti, Ombretta; Sugden, Conor; et al., "Defects in Lipid Homeostasis Reflect the Function of TANGO2 in Phospholipid and Neutral Lipid Metabolism" (2023). Faculty and Staff Publications. 5226.
https://digitalcommons.library.tmc.edu/baylor_docs/5226
Included in
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