Cysteine in Longevity-Related Redox Signaling
Some potentially damaging molecules are produced during the normal operation of metabolism. Cells have evolved numerous mechanisms to clean up that damage, but have also evolved to treat the presence of these damaging molecules as a part of the complex systems of signaling that regulate metabolism and cell maintenance. Thus when mitochondria are altered to produce a mild increase in reactive oxygen species (ROS), the usual byproduct of their production of the chemical energy store molecule adenosine triphosphate (ATP), cells react with increased maintenance and improved function. The end result in short-lived laboratory species such as nematodes and flies is a greater resilience to the damage of aging and a modestly extended life span. Researchers would like to tie this and similar exhibitions of mild stress producing a modest slowing of aging into a more unified big picture, and examining the oxidation of cysteine present in proteins in these processes is one step along that path.
Reactive oxygen species (ROS) and hydrogen sulfide (H2S) are naturally produced during metabolic processes. At physiological levels, they act as oxidation-reduction (redox) signaling molecules and regulate a myriad of cellular processes. Redox signaling occurs largely through rapid and reversible oxidation of reactive cysteine residues in target proteins, leading to changes in protein ligand binding affinity, subcellular localization, and function. Recent studies have demonstrated that ROS and H2S play an essential role in various longevity models, and that a mild increase in ROS or H2S levels is sufficient to extend lifespan in model organisms. Meanwhile, the number of aging-related proteins that are modulated by ROS- or H2S-mediated post-translational modification is constantly growing.
In this review, we aim to summarize key results that support cysteine-based redox regulation of organismal aging and lifespan. The human proteome contains ∼210,000 cysteine residues, and mass spectrometry-based chemoproteomics analyses reveal that thousands of cysteines are oxidant-sensitive. Under physiological conditions, ROS and H2S signaling are intrinsically connected via cysteine oxidation. For example, treating HeLa cells with EGF induces a transit increase in H2O2 production and promotes global sulfenylation, followed by a wave of proteome-wide cysteine persulfidation. H2O2-mediated sulfenylation of the active site cysteine Cys797 enhances EGF receptor (EGFR) tyrosine kinase activity, which is suppressed by pretreatment with H2S. These results suggest that ROS- and H2S-mediated cysteine modifications may play antagonistic roles in growth factor signaling, and raise an important question whether the crosstalk between ROS and H2S also exists in other processes including aging.