The Mode of Action of Enniatins A and B is Mediated by Interaction with SOC Reservoirs (A) and Mitochondrial Permeability Transition Pore (B)

Enniatins (ENNs) A and B have long been described as ionophores, but their mechanism of action remains unclear. In this study, their effects on Ca2+ fluxes and mitochondrial function were studied in SH-SY5Y human neuroblastoma cells. ENN A caused an acute Ca2+ depletion from intracellular pools and a significant Ca2+ influx from the extracellular media through store operated channels (SOC), confirmed with the SOC inhibitor SKF96365. ENN B also released Ca2+ from reservoirs, but it did not induce the ion influx. When thapsigargin (Tg)-dependent intracellular pools were modulated, Ca2+ influx induced by ENNs A and B was reduced between 38,8 and 51.4%, respectively. However, the mycotoxins acted differently. ENN A appears to act on the same reservoirs but in a different way than thapsigargin, while ENN B seems to affect thapsigargin-dependent pools similarly to the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). When incubating the cells with ENNs and FCCP, it was observed that ENN A affected mitochondrial Ca2 + fluxes and ENN B showed a similar behaviour to FCCP. Therefore, the effects of ENNs on mitochondrial permeability transition pore were determined, observing that both toxins induced the channel opening. Finally, in view of their different effects on calcium homeostasis, the combined effects of ENN A and ENN B on cell viability were determined, resulting in antagonism. This study describes for first time the distinct effects of ENNs A and B on Ca2 + fluxes, confirming that these toxins are not calcium ionophores and have a different mechanism of action.

Automated summary

This study investigates the effects of enniatins A and B on Ca2+ fluxes and mitochondrial function in human neuroblastoma cells. The results reveal that these toxins have distinct effects on Ca2+ fluxes and different mechanisms of action.