The mechanism underlying toxicity of a venom peptide against insects reveals how ants are master at disrupting membranes

Hymenopterans represent one of the most abundant groups of venomous organ-isms but remain little explored due to the difficult access to their venom. The development of proteo-transcriptomic allowed us to explore diversity of their toxins offering interesting perspectives to identify new biological active pep-tides. This study focuses on U9 function, a linear, amphiphilic and polycationic pep-tide isolated from ant Tetramorium bicarinatum venom. It shares physicochemical properties with M-Tb1a, exhibiting cytotoxic effects through membrane permea-bilization. In the present study, we conducted a comparative functional investiga-tion of U9 and M-Tb1a and explored the mechanisms underlying their cytotoxicity against insect cells. After showing that both peptides induced the formation of pores in cell membrane, we demonstrated that U9 induced mitochondrial damage and, at high concentrations, localized into cells and induced caspase activation. This functional investigation highlighted an original mechanism of U9 questioning on potential valorization and endogen activity in T. bicarinatum venom.