Deciphering the roles of cystathionine gamma-lyase/H2S system in Fe-S protein biogenesis and iron homeostasis

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Hydrogen sulfide (H2S) is traditionally known as a toxic gas but recently recognized as a ubiquitous signal molecule, which regulates a variety of physiological processes in many different species (from microbes to animals to human). H2S can be endogenously produced from the amino acid cysteine by a vitamin B6-dependent enzyme cystathionine gamma-lyase (CSE). H2S is capable of post-translational modification of proteins by yielding a hydropersulfide (-SSH) in the active cysteine residues, termed as S-sulfhydration. Fe-S clusters are the most ancient redox centers for numerous proteins involved in energy production, oxygen transport, DNA replication and repair in all kingdoms of life. Another highly conserved vitamin B6-dependent enzyme cysteine desulfurase (NFS1) can decompose cysteine for the very first step of Fe-S cluster biosynthesis. Given the facts that CSE and NFS1 share many similar chemical features and H2S and iron are mutually dependent in the regulation of cellular functions, it is indispensable to investigate the interconnections among H2S signals, iron metabolism, and Fe-S cluster formation in mammalian cells.         My long-term goal is to elucidate the biological importance of H2S in order to improve our understanding of the regulation of a multitude of cellular functions, and to better train the next generation of researchers in this field. The short-term goal, through this research program, is to determine the interaction of H2S metabolism and Fe-S protein biogenesis in iron homeostasis and iron-dependent cell death (ferroptosis) under various stress conditions.         Two specific objectives are proposed in this program: 1) investigate the regulation of CSE/H2S system on NFS1 functions and Fe-S cluster biosynthesis and stability; 2) examine the role of CSE/H2S system in iron metabolism and ferroptosis sensitivity under stress conditions (low oxygen and iron overload/deprivation). In combination with genetic, biochemical, spectroscopic, and mechanistic studies in both skeletal muscle cells and heart cells, this program may lead to new paradigms in the understanding of H2S signals and Fe-S protein biogenesis in mammalian cells.