Patulin induces crosstalk between ferroptosis and the endoplasmic reticulum-MAMs-mitochondria axis in the kidney

Patulin (PAT), a prevalent mycotoxin. It is widely present in fruits and nuts and causes serious harm to human health. Our prior study found that PAT exposure could trigger ferroptosis, which in turn resulted in severe kidney damage. However, the specific mechanism remained unclear. This research was designed to explore the molecular mechanisms responsible for PAT-induced renal ferroptosis. In vivo, Western blot analysis revealed that PAT exposure activated ferroptosis and endoplasmic reticulum (ER) stress, and reduced the expression of mitochondria-associated endoplasmic reticulum membranes (MAMs)-associated proteins. Specific commercial detection kits revealed a decrease in tissue adenosine triphosphate (ATP) content and an increase in iron content. Transmission electron microscopy (TEM) observation showed that PAT disrupted the structure of MAMs. In vitro, PAT exposure activated the PERK-related ER stress pathway in mouse kidneys and disrupted both the structure of MAMs and normal mitochondrial function. Molecular docking revealed a strong interaction between MFN2 and MFN1. ER stress inhibition in PAT-treated HKC cells elevated MAMs-related protein expression, which in turn restored mitochondrial membrane potential (MMP) and lowered Mitochondrial Reactive Oxygen Species (MtROS) levels. Similarly, MFN2 overexpression restored mitochondrial function and inhibited ferroptosis. Our study demonstrated that ER stress and MAMs integrity lay at the heart of PAT-induced mitochondrial failure and ferroptosis. The results identified a new mechanism through which PAT triggered ferroptosis, offering fresh perspectives on the pathogenesis of mycotoxin-induced kidney injury.