Mitochondrial production and function of hydrogen sulphide

线粒体是一种双膜封闭的胞内细胞器，是真核细胞通过氧化磷酸化产生ATP的动力源。在上一次nserc资助期间，我们提供了充足的证据，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，由一种名为半胱硫氨酸γ -裂解酶（CSE）的酶催化。CSE通常位于细胞的细胞质和线粒体中。我们假设在不同的能量需求条件下，CSE在细胞质和线粒体之间的分配，即再分配，发生了变化。CSE及其产物H2S的再分配有可能影响哺乳动物细胞的能量产生和存活。这个程序将阐明这种CSE在细胞内重新分配的功能后果。我们的目标是研究1)不同应激条件下线粒体CSE的定位、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。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的线粒体位置及其在不同能量需求条件下的再分布。在项目2中，关于这种CSE线粒体易位如何发生的问题将得到解决。CSE重新分配后线粒体的功能变化将是Project 3的重点。最后，Project 4将致力于测定H2S与线粒体不同结构组分的相互作用。这个项目可能会导致我们对哺乳动物细胞基本硫代谢，线粒体的进化和病因学，以及动物和人类心血管系统线粒体生物发生和功能调控的理解取得突破。

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.