Regulation of Mitochondrial function by hydrogen sulfide

线粒体作为双膜封闭的细胞内细胞器，是真核细胞的动力库，通过氧化磷酸化产生ATP。已知硫化氢(H_2S)可以降低哺乳动物细胞的氧化应激和对ATP的利用。血管平滑肌细胞以L-半胱氨酸或同型半胱氨酸为底物，胞浆中的胱硫醚-γ-裂解酶(CSE)催化产生H_2S。我们假设线粒体产生H_2S是通过CSE在不同代谢应激条件下移位到线粒体来实现的，线粒体H_2S参与了线粒体功能的调节。测试这些假说的努力得到了我之前从NSERC获得的发现拨款的支持。我们已经获得了CSE蛋白在不同代谢条件下从胞浆转运到线粒体的确凿证据。我们还发现，L半胱氨酸在线粒体中的浓度显著高于胞浆中的浓度。一旦移位到线粒体内，CSE就会使用线粒体半胱氨酸来产生硫化氢，改变线粒体的能量和生物发生。我们的目标是研究1)不同应激条件下线粒体CSE的易位和H_2S的产生，以及2)H_2S在线粒体结构和功能调节中的作用及其潜在机制。在哺乳动物细胞中，线粒体H_2S的产生及其生物学意义，与胞浆中的H_2S相比，从未被研究过。这个程序有可能揭开线粒体中CSE/H2S新的重要功能的面纱。此外，它可能导致我们对哺乳动物细胞中基本的硫代谢、线粒体的进化和病因学以及动物和人类心血管系统中线粒体的生物发生和功能调节的认识上的突破。

Being the double-membrane enclosed intracellular organelles, mitochondria are the power house of eukaryotic cells where ATP is produced via oxidative phosphorylation. It has been known that both oxidative stress and ATP utilization in mammalian cells can be reduced by hydrogen sulfide (H2S). Vascular smooth muscle cells use L-cysteine or homocysteine as substrates to produce H2S, catalyzed by cystathionine gamma-lyase (CSE) in cytosol. We have hypothesized that mitochondrial production of H2S can be realized by translocation of CSE to mitochondria in response to different metabolic stress conditions; and mitochondrial H2S is involved in the regulation of mitochondria functions. The effort to test these hypotheses has been supported by my previous Discovery Grants from NSERC. We have obtained solid evidence that CSE protein is translocated from cytosol to mitochondria under different metabolic conditions. We also found that the concentration of L-cysteine in mitochondria is significantly higher than that in the cytosol. Once translocated inside mitochondria, CSE uses mitochondrial cysteine to produces H2S, altering mitochondrial energization and biogenesis. Our objectives are to examine 1) mitochondrial CSE translocation and H2S production under different stress conditions, and 2) the role of H2S in regulation of mitochondrial structure and function as well as the underlying mechanisms. Mitochondrial H2S production and its biological importance, in comparison with that in the cytosol, in mammalian cells have never been examined. This program has the potential to unmask the novel and important function of CSE/H2S in mitochondria. Moreover, it may lead to a breakthrough in our understanding of the fundamental sulfur metabolism in mammalian cells, of the evolution and etiology of mitochondria, and of the regulation of mitochondrial biogenesis and function in animal cardiovascular system as well as that of humans.