bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.11.05.515282

Defects in lipid homeostasis reflect the function of TANGO2 in Acyl-CoA metabolism

Lujan, A. L.·Foresti, O.·Brouwers, N.·Mateo Farre, A.·Vignoli, A.·Wojnacki, J.·Malhotra, V.
View original source ↗Export metadata ↓

Abstract

We show that TANGO2, which lacks a transmembrane domain localizes predominantly to mitochondria and transiently to endoplasmic reticulum (ER) and lipid droplets (LDs). Evaluation of lipids in HepG2 cells lacking TANGO2 revealed an increase in the size of lipid droplets and reactive oxygen species production. There is also a marked increase lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes are exacerbated in nutrient starved cells. Based on our data, we suggest that the principle function of TANGO2 is in acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. This defect subsequently affects metabolism of many other fatty acids. These data help explain the physiological consequence of TANGO2 that induce acute metabolic crisis including rhabdomyolysis, cardiomyopathy and cardiac arrhythmias often leading to fatality upon starvation and stress.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lujan, A. L., Foresti, O., Brouwers, N., Mateo Farre, A., Vignoli, A., Wojnacki, J., Malhotra, V.. 2022-11-05. Defects in lipid homeostasis reflect the function of TANGO2 in Acyl-CoA metabolism. https://doi.org/10.1101/2022.11.05.515282

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Sequence context and partner availability specify divergent cell fates from a single transcription factor

Transcription factors drive the gene regulatory networks that control developmental transitions, yet which of their many targets a cell uses remains unresolved. Expressing Cebp, Cebp{beta} or Cebp{delta} identically, alone or with Oct4, Sox2, Klf4 and cMyc, gave four outcomes: adipocyte from fibroblasts and neural stem cells, trophectoderm from embryonic stem cells, and myeloid from B cells. Raising Cebp levels changed how many sites it reached, not which sequence it read: clustered motifs maintained somatic enhancers, while spillover onto low-copy sites created de novo enhancers carrying composites of Cebp and cell-type-restricted partners. In fibroblasts, Cebp also redistributed Oct4, Sox2 and Klf4 from early targets, blocking iPSC formation. Supplying the predicted partners rewrote the output: Spi1 redirected Cebp into parallel adipogenic and myeloid programs, via a transient PpargCD45 state using separate enhancers for each; TFAP2C abolished adipogenic conversion. Motif density and partner composites therefore assemble a factor's instructive output in the receiving cell.

cell biology↗
bioRxiv2026

High-content screening identifies FDA-approved activators of mitophagy

Mitochondrial diseases are highly heterogeneous disorders caused by defects in oxidative phosphorylation, for which only limited therapeutic options are available. The elimination of dysfunctional mitochondria via mitophagy activation is an attractive strategy to treat several mitochondrial diseases, irrespective of the underlying genetic defect. To identify pharmacological activators of this pathway, we performed a high-content screening of 1,971 FDA-approved compounds using cellular reporters of TFEB nuclear translocation and mitophagy. This screening identified 294 compounds that promoted TFEB translocation, nine of which increased the number of mitolysosomes without compromising cell viability or damaging mitochondria. Among the selected compounds, Meptazinol and Ponatinib emerged as the top-ranked mitophagy inducers in fibroblasts from patients with complex I and IV deficiency, respectively, and were prioritised for further characterisation. However, they did not rescue the bioenergetic defect, suggesting that the stimulation of mitophagy per se is not sufficient to ameliorate the OXPHOS defect in mitochondrial diseases. Overall, our findings establish a scalable platform for the identification of pharmacological activators of TFEB and identify candidate compounds for therapeutic modulation of mitophagy.

cell biology↗
bioRxiv2026

Matrix Gla Protein deficiency reveals a previously unrecognized mucosal calcification in the mouse airways

Tracheal calcification is a common finding that is considered to have limited clinical significance when detected most often in elderly individuals. Despite its frequent occurrence, the cellular and molecular mechanisms at the origin of tracheal calcification remain largely unexplored. In this context, we aimed to characterize the development of tracheal calcification, and to determine the role of matrix Gla protein (MGP), a major inhibitor of ectopic calcification whose genetic or pharmacologic deficiency is associated with premature tracheal calcification in humans. We found that wild-type mice undergo an unexpected early physiologic calcification of the tracheal cartilage rings beginning around one month after birth. This calcification progresses in a dynamic rostro-caudal sequence through a process involving terminal differentiation of tracheal chondrocytes. These findings challenge the prevailing view that tracheal cartilage is a permanent hyaline cartilage and instead reveals an early and highly organized physiologic calcification process. Furthermore, our findings further identify MGP as a key regulator of calcification within the respiratory tract. Indeed, MGP deficiency not only markedly accelerates tracheal cartilage calcification through a similar pattern and mechanism but also induces a previously unrecognized calcification of the tracheal mucosa, a lesion absent in wild-type mice. These alterations could partly explain the respiratory manifestations observed in MGP-deficient patients having Keutel syndrome, which include dyspnea, cough, stridor, and recurrent infections, symptoms previously being mainly attributed to calcification of the tracheal cartilage rings.

cell biology↗