Mitochondrial production and function of hydrogen sulphide

线粒体是一种双膜封闭的细胞器，是真核细胞的动力室，通过氧化磷酸化产生ATP。在上一个NSERC支持的资助期间，我们提供了充分的证据证明硫化氢（H2S）对细胞代谢和功能的生理重要性。这种内源性气体分子由L-半胱氨酸产生，由一种名为胱硫醚γ-裂解酶（CSE）的酶催化。CSE通常位于细胞的胞浆和线粒体中。 我们假设，在各种能量需求条件下，CSE在细胞质和线粒体之间的分配，即重新分配，发生变化。 CSE及其产物H2S的这种重新分布有可能影响哺乳动物细胞的能量产生和存活。该计划将阐明这种CSE在细胞内重新分布的功能后果。我们的目标是研究1）在不同胁迫条件下线粒体CSE的定位和易位以及H2S的产生，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。本研究计划由4个相互关联的项目组成，在培养的大鼠血管平滑肌细胞上进行。项目1将研究CSE的线粒体定位及其在不同能量需求条件下的再分布。在项目2中，将解决CSE线粒体易位如何发生的问题。 CSE再分布后线粒体的功能变化将是项目3的重点。最后，项目4将致力于确定H2S与线粒体不同结构组分的相互作用。这一计划可能会导致我们在哺乳动物细胞中的基本硫代谢，线粒体的进化和病因学，以及动物心血管系统和人类的线粒体生物发生和功能的调节的理解上取得突破。

Being a double-membrane enclosed intracellular organelle, mitochondrion is the power house of eukaryotic cells where ATP is produced via oxidative phosphorylation. During the last NSERC-supported funding period, we have provided ample evidence for the physiological importance of hydrogen sulfide (H2S) for cellular metabolism and functions. This endogenous molecule of gas is produced from L-cysteine, catalyzed by an enzyme named cystathionine gamma-lyase (CSE). CSE usually is located in both the cytosol and mitochondria of the cells. We hypothesize that under various energy demanding conditions the allocation of CSE between the cytosol and mitochondria, i.e. redistribution, changes. This redistribution of CSE and its product H2S have the potential to affect the energy production and the survival of mammalian cells. This program will elucidate the functional consequence of this CSE redistribution inside the cells. Our objectives are to examine 1) mitochondrial CSE location and 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. This research program is composed of 4 interlinked projects, conducted on cultured rat vascular smooth muscle cells. Project 1 will investigate the mitochondrial location of CSE and its redistribution under different energy demanding conditions. In Project 2, the question as to how this CSE mitochondrial translocation occurs will be addressed. The functional changes of mitochondria after this CSE redistribution will be the focus of Project 3. Finally, Project 4 will be devoted to the determination of the interaction of H2S with different structural components of mitochondria. This program may lead to a breakthrough in our understanding of 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 human's.