Grant: Discovery Grants Program - Individual

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.