Regulation of Mitochondrial function by hydrogen sulfide

硫化氢对线粒体功能的调节

• 批准号: 171409-2012
• 负责人: Wang, Rui
• 金额: $ 3.42万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=569617
• 关键词: Regulation; Mitochondrial; function; hydrogen; sulfide

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.

线粒体是真核细胞内的双膜结构细胞器，是真核细胞的发电厂，通过氧化磷酸化产生ATP。众所周知，硫化氢（H2S）可以降低哺乳动物细胞中的氧化应激和ATP利用率。 血管平滑肌细胞使用L-半胱氨酸或同型半胱氨酸作为底物，在胞质溶胶中由胱硫醚γ-裂解酶（CSE）催化产生H2S。 我们假设线粒体产生H2S可以通过响应于不同的代谢应激条件将CSE易位到线粒体来实现;并且线粒体H2S参与线粒体功能的调节。我之前从NSERC获得的发现赠款支持了对这些假设的验证。 我们已经获得了坚实的证据，CSE蛋白从细胞质转运到线粒体在不同的代谢条件。我们还发现，L-半胱氨酸的浓度在线粒体中显着高于在细胞质中。 一旦在线粒体内易位，CSE使用线粒体半胱氨酸产生H2S，改变线粒体的生物合成和生物发生。我们的目标是研究1）在不同胁迫条件下线粒体CSE易位和H2S产生，和2）H2S在线粒体结构和功能调节中的作用以及潜在的机制。线粒体H2S的生产和它的生物学意义相比，在胞质溶胶中，在哺乳动物细胞中从未被检查。该程序有可能揭示CSE/H2S在线粒体中的新的和重要的功能。此外，它可能会导致我们在理解哺乳动物细胞中的基本硫代谢，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生物发生和功能的调节方面取得突破。