May the post-translational process of succination be involved in cardiotoxicity?

The small ubiquitin-like modification (SUMO) process represents a reversible and very dynamic post-translational modification (PTM) conserved across all eukaryotes. This PTM plays an important role in the regulation of proteins involved in various fundamental cellular processes. Of all SUMO family members, SUMO1 is responsible for SUMOylating, among others, the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), which is responsible of facilitating the reuptake of Ca2+ in the endoplasmic reticulum after cardiac contraction. This study aims to investigate if succination, an irreversible PTM resulting from the interaction of fumarate with reactive cysteine thiols, is responsible for influencing the function of SUMO1. Such modifications may, in turn, have downstream effects on the function of SERCA2a, and consequently on heart contraction. To explore his, we utilized fumaric acid treatment to increase intracellular fumarate levels in AC16 cardiomyocytes. This approach allows the evaluation of the function of the succinated SUMO1 and its function in SUMOylating proteins, particularly in SUMOylating SERCA2a. evaluation includs a combination of metabolomic analysis, gene expression profiling and protein assessment techniques. Initial findings from an in-vitro SUMOylation/succination reaction, suggest a possible decrease in SUMOylation of SERCA2a by succinated SUMO1. In conclusion, understanding the impact of SUMO1 succination on SERCA2a SUMOylation, could reveal a new regulatory mechanism in cardiac function, and this might allow a better understanding of the heart physiopathology.