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Siderophores induce mitophagy-dependent apoptosis in platelets.

Background
Siderophores are major virulent factors of K. pneumoniae, and their roles are iron chelators in the host. Several studies have shown that iron chelation could result in mitochondrial dysfunction and increase the production of reactive oxygen species (ROS), which further induces cell mitophagy and apoptosis. However, the impacts of siderophores on platelets are still unknown.


Methods
We obtained platelets of healthy volunteers to perform in vitro experiments in our study and treated platelets with different siderophores. Mitophagy related proteins (TOMM20, TIMM23, LC3, and p62), signal proteins (PINK1/Parkin and BNIP3), and apoptosis protein (caspase3) in platelets were analyzed by western blot. The co-localization of mitotracker with LC3-II was analyzed by immunofluorescence assays. The flow cytometer was used to evaluate ROS levels.


Results
All four kinds of siderophores (10 μM) secreted by K. pneumoniae increased the expression of LC3 II and reduced the expression of mitochondrial membrane protein, TOMM20, and TIMM23. Immunofluorescence assays revealed that the treatment of enterobactin significantly increased the co-localization of mitotracker with LC3-II. All four kinds of siderophores increased the ROS level in platelets. Mitophagy of platelets was activated through several pathways, including PINK1/Parkin- and BNIP3-dependent pathways. We also proved that siderophores increased the expression of caspase3 in platelets, and the expression of caspase3 significantly decreased after the pathways of mitophagy were blocked.


Conclusions
K. pneumoniae siderophores lead to mitophagy in platelets, and mitophagy further induces apoptosis, which may be a potential treatment of thrombocytopenia in infections.