Haem's relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans.
Haem's relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans.
复制标题
海姆的相关性是真的吗？
DOI：
10.1101/2023.11.29.569072
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Mackenzie,SamuelJ
中科院分区：
文献类型：
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作者：
Sandkuhler,SarahE;Youngs,KaylaS;Owlett,Laura;Bandora,MonicaB;Naaz,Aaliya;Kim,EuriS;Wang,Lili;Wojtovich,AndrewP;Gupta,VandanaA;Sacher,Michael;Mackenzie,SamuelJ
TANGO 2基因突变会导致人类严重疾病，包括危及生命的代谢危机。然而，TANGO 2蛋白的功能仍然未知。使用秀丽隐杆线虫和其他模型，最近有人提出TANGO 2在细胞内和细胞间运输血红素，从血红素浓度高的区域运输到浓度较低的区域。在这里，我们表明，血红素相关的观察线虫可能会更好地解释以前未报告的代谢表型在这些蠕虫，其特征在于减少喂养，寿命和育雏大小，和运动性差。我们还发现，在血红素水平较低时，一些与血红素转运无关的基因表达上调，相反，hrg-9对氧化应激反应强烈，与血红素水平无关。总的来说，这些数据表明生物能量衰竭和氧化应激是TANGO 2缺乏症病理生理学的关键因素，与人类患者的观察结果一致。我们的研究小组在缺乏TANGO 2同源物的酵母和斑马鱼中进行了几项实验，但无法复制这些模型的先前发现。总的来说，我们认为没有足够的证据支持血红素转运作为TANGO 2的主要功能。
Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises. However, the function of TANGO2 protein remains unknown. Using Caenorhabditis elegans and other models, it has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that heme-related observations in nematodes may be better explained by a previously unreported metabolic phenotype in these worms, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as key factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.