Lipidomic analysis of human TANGO2-deficient cells suggests a lipid imbalance as a cause of TANGO2 deficiency disease

Mehranfar, Mahsa; Asadi, Paria; Shokohi, Rozmehr; Milev, Miroslav P.; Gamberi, Chiara; Sacher, Michael

doi:10.1016/j.bbrc.2024.150047

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Preliminary lipidomic analysis from our group ( Mehranfar et al, 2024 ) revealed a significant increase in the abundance of unsaturated free fatty acids, neutral lipids, sphingomyelins, and phospholipids in primary human TANGO2-deficient fibroblasts harboring the exon 3-9 deletion commonly found in patients with TDD, compared to the levels seen in control cells. This increase was particularly notable for triglycerides, diacylglycerides and ceramides, which was further exacerbated during glucose starvation, suggesting a potential defect in lipid consumption when cells need fatty acids for energy release.…”

Section: Vitamin B Treatment Indicates That Lipid Homeostasis Defects...mentioning

confidence: 96%

TANGO2 deficiency disorder is predominantly caused by a lipid imbalance

Sacher,

DeLoriea,

Mehranfar

et al. 2024

Disease Models &Amp; Mechanisms

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TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

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Section: Vitamin B Treatment Indicates That Lipid Homeostasis Defects...mentioning

confidence: 96%

TANGO2 deficiency disorder is predominantly caused by a lipid imbalance

Sacher,

DeLoriea,

Mehranfar

et al. 2024

Disease Models &Amp; Mechanisms

Self Cite

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Cellular mechanisms of acute rhabdomyolysis in inherited metabolic diseases

de Calbiac,

Imbard,

de Lonlay

2024

J of Inher Metab Disea

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Acute rhabdomyolysis (RM) constitutes a life‐threatening emergency resulting from the (acute) breakdown of skeletal myofibers, characterized by a plasma creatine kinase (CK) level exceeding 1000 IU/L in response to a precipitating factor. Genetic predisposition, particularly inherited metabolic diseases, often underlie RM, contributing to recurrent episodes. Both sporadic and congenital forms of RM share common triggers. Considering the skeletal muscle's urgent need to rapidly adjust to environmental cues, sustaining sufficient energy levels and functional autophagy and mitophagy processes are vital for its preservation and response to stressors. Crucially, the composition of membrane lipids, along with lipid and calcium transport, and the availability of adenosine triphosphate (ATP), influence membrane biophysical properties, membrane curvature in skeletal muscle, calcium channel signaling regulation, and determine the characteristics of autophagic organelles. Consequently, a genetic defect involving ATP depletion, aberrant calcium release, abnormal lipid metabolism and/or lipid or calcium transport, and/or impaired anterograde trafficking may disrupt autophagy resulting in RM. The complex composition of lipid membranes also alters Toll‐like receptor signaling and viral replication. In response, infections, recognized triggers of RM, stimulate increased levels of inflammatory cytokines, affecting skeletal muscle integrity, energy metabolism, and cellular trafficking, while elevated temperatures can reduce the activity of thermolabile enzymes. Overall, several mechanisms can account for RMs and may be associated in the same disease‐causing RM.

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Heme’s relevance genuine? Re-visiting the roles of TANGO2 homologs including HRG-9 and HRG-10 inC. elegans

Sandkuhler,

Youngs,

Owlett

et al. 2023

Preprint

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Mutations in theTANGO2gene cause severe illness in humans, including life-threatening metabolic crises; however, the function of TANGO2 protein remains unknown. In a recent publication inNature, Sun et al. proposed that TANGO2 helps transport haem within and between cells, from areas with high haem concentrations to those with lower concentrations.Caenorhabditis eleganshas two versions of TANGO2 that Sun et al. called HRG-9 and HRG-10. They demonstrated that worms deficient in these proteins show increased survival upon exposure to a toxic haem analog, which Sun et al. interpreted as evidence of decreased haem uptake from intestinal cells into the rest of the organism. We repeated several experiments using the sameC. elegansstrain as Sun et al. and believe that their findings are better explained by reduced feeding behavior in these worms. We demonstrate thathrg-9in particular is highly responsive to oxidative stress, independent of haem status. Our group also performed several experiments in yeast and zebrafish models of TANGO2 deficiency and was unable to replicate key findings from these models reported in Sun et al.’s original study. Overall, we believe there is insufficient evidence to support haem transport as the primary function for TANGO2.

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Lipidomic analysis of human TANGO2-deficient cells suggests a lipid imbalance as a cause of TANGO2 deficiency disease

Cited by 3 publications

References 16 publications

TANGO2 deficiency disorder is predominantly caused by a lipid imbalance

TANGO2 deficiency disorder is predominantly caused by a lipid imbalance

Cellular mechanisms of acute rhabdomyolysis in inherited metabolic diseases

Heme’s relevance genuine? Re-visiting the roles of TANGO2 homologs including HRG-9 and HRG-10 inC. elegans

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