HRG-9 homologues regulate haem trafficking from haem-enriched compartments

Sun, Fengxiu; Zhao, Zhenzhen; Willoughby, Mathilda M.; Shen, Shuaiqi; Zhou, Yu; Shao, Yiyan; Kang, Jing; Chen, Yongtian; Chen, Mengying; Yuan, Xian‐You; Hamza, Iqbal; Reddi, Amit R.; Chen, Caiyong

doi:10.1038/s41586-022-05347-z

Cited by 40 publications

(75 citation statements)

References 56 publications

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“…Haem metabolism is critical for skeletal muscle function and mitochondria defects observed in our t ango2 mutants may affect haem metabolism (Alves de Souza et al, 2021). However, a lack of difference in haem synthesis in control and tango2 mutant fish in the previous study suggests TANGO2 is not required for in vivo haem metabolism in vertebrates (Sun et al, 2022). In addition, we found many differences between tango2 mutants reported in the previous study and tango2 mutants presented in this work.…”

Section: Discussionmentioning

confidence: 78%

“…Finally, the previous study showed that mutants obtained from mutant parents exhibited extensive defects in the brain, skeletal muscle and heart and die during the first two weeks of development. We also analyzed the tango2 mutants obtained from tango2 mutant parents in our zebrafish lines and did not see any defects in the brain, skeletal muscle and heart in the basal state as reported previously (Sun et al, 2022). Since different sgRNAs were used to create fish lines in ours and the previous study, we cannot rule out the possibility of some genetic background effect.…”

Section: Discussionmentioning

confidence: 84%

“…A recent study showed that TANGO2 orthologue HRG-9 is critical for haem trafficking in C. elegans and deficiency of HRG-9 contributes to haem overload in mitochondria (Sun et al, 2022). Haem metabolism is critical for skeletal muscle function and mitochondria defects observed in our t ango2 mutants may affect haem metabolism (Alves de Souza et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found many differences between tango2 mutants reported in the previous study and tango2 mutants presented in this work. Sun et al, 2022 showed that tango2 zebrafish mutants obtained from heterozygous mating were able to grow to adulthood with no obvious phenotype and display normal survival which was attributed to the extended stability of maternal mRNA. This contrasts with our findings which demonstrate tango2 zebrafish mutants obtained from heterozygous matings exhibit reduced survival from the larval stage (80% at 6 dpf) to 4% by 3 months of age (n=350) (Figure 1D).…”

Section: Discussionmentioning

confidence: 99%

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Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Casey

Kim

Tao

et al. 2022

Preprint

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Rhabdomyolysis is a clinical emergency characterized by severe muscle damage resulting in the release of intracellular muscle components leading to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations inTANGO2result in episodic rhabdomyolysis, metabolic crises, encephalopathy and cardiac arrhythmia, the underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we show that loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of muscle defects similar toTANGO2patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state oftango2mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and increased our understanding of how specific defects can predispose to environmental triggers in TANGO2-related disorders.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Casey

Kim

Tao

et al. 2022

Preprint

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“…27 In this respect it is noteworthy that a recent study suggests TANGO2 may act as a heme chaperone, moving this iron-containing molecule out of the mitochondria. 28 If so, it remains to be determined how a TDD trigger relates to heme transport and a metabolic crisis, and why brain iron accumulation is not seen in TDD affected individuals.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B5, a Coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects inDrosophilaand human cells

Asadi

Milev

Saint‐Dic

et al. 2022

Preprint

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Mutations in the Transport and Golgi Organization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model of TANGO2-related disease in the fruit fly Drosophila melanogaster that recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a Coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated with TANGO2 deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function in Drosophila and rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed including restoration of lipid homeostasis.

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Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease‐associated defects in Drosophila and human cells

Asadi

Milev

Saint‐Dic

et al. 2022

J of Inher Metab Disea

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HRG-9 homologues regulate haem trafficking from haem-enriched compartments

Cited by 40 publications

References 56 publications

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Vitamin B5, a Coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects inDrosophilaand human cells

Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease‐associated defects in Drosophila and human cells

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