TANGO调控血红素稳态的分子机理研究

Heme is an iron-containing cofactor for a variety of proteins such as hemoglobin, myoglobin, and cytochromes. It plays essential roles in numerous biological processes including oxygen transport, electron transport, gas sensing, xenobiotic detoxification, signal transduction, microRNA processing, and circadian clock control. Cellular heme is either taken up through the plasma membrane or synthesized within the mitochondria. It needs to be translocated to other subcellular compartments where hemoproteins such as hemoglobins, catalases, and peroxidases reside. Through a reverse genetics screen, we identified two previously uncharacterized genes termed tngo-a and tngo-b which are both upregulated under heme deficiency in C. elegans. Genetic and cellular studies indicate that TNGOs play important roles in regulating intracellular heme homeostasis in worms. The TANGO family is highly conserved in animals. Our preliminary work in mammalian cells suggests that human TANGO is also critical for maintaining heme homeostasis. The main objective of this proposal is to dissect the molecular function of vertebrate TANGO using a combination of genetic, biochemical, and cell biological approaches. We hypothesize that TANGO is an intracellular heme chaperone that regulates heme transfer among subcellular compartments. Results from this proposal will fill in gaps in the field of intracellular heme trafficking, broaden the basic understanding of heme metabolism as well as membrane trafficking, and provide new genetic basis for understanding and treating heme-related human diseases such as anemias.

血红素是所有生物都必需的一种含铁卟啉化合物，它在氧气运输、电子传递、信号转导等细胞活动中发挥重要功能。血红素来源于线粒体合成或细胞膜吸收，它需要依赖特定分子通路被转运到其它亚细胞部位，以供给血红蛋白、过氧化氢酶、过氧化物酶等血红素蛋白。目前细胞内血红素运输通路尚不清楚。我们在模式动物秀丽线虫上发现两个新的血红素感应基因tngo-a和tngo-b，它们调控机体血红素稳态。TANGO基因家族在动物上高度保守。我们通过初步研究，发现人的TANGO也与血红素稳态代谢密切相关。本项目将在前期研究基础上，以体外细胞和斑马鱼为研究体系，结合遗传学、细胞生物学、生物化学等实验手段，解析TANGO在血红素稳态调控中的生理功能和分子机制。预期TANGO是一个血红素分子伴侣，调控亚细胞水平血红素转运。研究结果有望阐明血红素出线粒体的分子机制，填补细胞内血红素运输领域的空白，为防治血红素代谢相关疾病提供理论依据。

血红素是所有生物必需的一种含铁卟啉化合物，它除了运输氧气外，还参与细胞呼吸、信号转导、基因表达调控、昼夜节律调控等很多生物学过程。血红素来源于线粒体合成或细胞膜吸收，它需要依赖特定分子通路被转运到各个亚细胞部位。我们通过前期研究在模式动物秀丽线虫上发现两个新的血红素感应基因hrg-9和hrg-10，它们调控线虫的血红素稳态。这两个基因在其它物种中有一个同源基因，叫TANGO2。本项目在前期研究基础上，以体外细胞和斑马鱼为研究体系，结合遗传学、细胞生物学、生物化学等实验手段，研究了TANGO2在血红素稳态调控中的生理功能和分子机制。本项目获得的重要研究结果包括：（1）敲除TANGO2引起哺乳动物细胞线粒体中血红素的累积；（2）tango2缺失后，斑马鱼幼鱼出现心、脑、肌肉等组织的病理变化，并于发育早期死亡；（3）TANGO2蛋白能结合血红素并将血红素转出线粒体。鉴于TANGO2是一个非跨膜蛋白，本项目的实验数据表明，TANGO2是一个新的血红素伴侣蛋白，在脊椎动物细胞中负责将血红素转运出线粒体，以供给其它亚细胞部位利用。本研究解析了TANGO2的生物学功能，阐明了血红素转出线粒体的重要机制，有力推动了对血红素代谢和细胞物质运输的认识。人TANGO2基因的突变会引起一种罕见的遗传性疾病，而目前TANGO2突变的致病机制仍不清楚。本研究的成果为理解TANGO2疾病的病理学机制奠定了一定的生物学基础。