H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells.

Hydrogen sulfide (H2S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.

Hydrogen sulfide and metal interaction: the pathophysiological implications.

Hydrogen sulfide (H2S), previously recognized as a toxic gas, has emerged as an important gaseous signaling molecule along with nitric oxide, carbon monoxide and also hydrogen. H2S can be endogenously produced in the mammalian body at a very low level for various pathophysiological processes. Notably, H2S can interact with several essential metals in the body such as iron, copper, nickel, and zinc to carry out specific functions. The interactions of H2S with metal-binding proteins have been shown to aid in its signal transduction and cellular metabolism. In addition, H2S is capable of providing a cytoprotective role against metal toxicity. As the research in the field of H2S signaling in biology and medicine increases, much progresses have been developed for detecting H2S via interaction with metals. In this review, the interaction of H2S with metals, specifically in regard to metal-driven metabolism of H2S, the protection against metal toxicity by H2S and the detection of H2S using metals will be discussed. Discovering the interactions of this gasotransmitter with metals is important for determining the mechanisms underlying the cellular functions of H2S as well as developing novel therapeutic avenues.