Regulation of Mitochondrial function by hydrogen sulfide

作为双膜封闭的胞内细胞器，线粒体是真核细胞通过氧化磷酸化产生ATP的动力源。众所周知，硫化氢（H2S）可以降低哺乳动物细胞的氧化应激和ATP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，在胞浆中由半胱甘氨酸γ -裂解酶（CSE）催化生成H2S。我们假设，在不同的代谢应激条件下，线粒体可以通过将CSE易位到线粒体来实现H2S的产生；线粒体H2S参与线粒体功能的调节。测试这些假设的努力得到了我以前从NSERC获得的发现基金的支持。我们已经获得了确凿的证据，证明CSE蛋白在不同的代谢条件下从细胞质转运到线粒体。我们还发现线粒体中l -半胱氨酸的浓度明显高于胞浆中的浓度。一旦在线粒体内易位，CSE利用线粒体半胱氨酸产生H2S，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易位和H2S的产生，以及2)H2S在线粒体结构和功能调节中的作用及其潜在机制。与细胞质相比，哺乳动物细胞中线粒体H2S的产生及其生物学重要性从未被研究过。该程序有可能揭示线粒体中CSE/H2S的新功能和重要功能。此外，它可能会使我们对哺乳动物细胞硫代谢的基本机制、线粒体的进化和病因、动物和人类心血管系统线粒体的生物发生和功能调控等方面的认识取得突破性进展。

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.