Mechanism of PISD/SPG7-mediated mPTP opening in necroptosis of inflammatory HaCaT cells induced by nano-zinc oxide.

Abstract

Zinc oxide nanoparticles (ZNPs) are extensively used in cosmetics and topical medications and are considered safe for normal skin. However, patients with inflammatory dermatoses, who have an impaired skin barrier, may be at increased risk of percutaneous exposure to ZNPs. Limited research currently exists on the percutaneous toxicity of ZNPs in such conditions. Therefore, this study aimed to evaluate the safety of ZNPs in inflammatory dermatoses. ZNP treatment increased inflammatory human immortalised keratinocyte (HaCaT) cell death and significantly elevated phosphorylated mixed lineage kinase domain-like protein (p-MLKL) protein expression in a concentration-dependent manner, showing that ZNPs trigger necroptosis in HaCaT cells. Further exploration revealed that ZNPs induced mitochondrial swelling and rupture and abnormal opening of the mitochondrial permeability transition pore (mPTP) in inflammatory HaCaT cells as well as decreased the expression of spastic paraplegia 7 (SPG7), a critical protein of the mPTP. Furthermore, phosphatidylserine decarboxylase (PISD) expression in the inner mitochondrial membrane (IMM) was significantly reduced. SPG7 overexpression reversed mPTP opening and necroptosis, whereas PISD overexpression directly upregulated SPG7 expression, inhibited mPTP opening, and reversed necroptosis. Our results indicate that ZNPs contribute to mPTP opening and mitochondrial swelling and rupture via the PISD/SPG7 pathway, an important mechanism leading to necroptosis in inflammatory HaCaT cells. Overall, this study highlights the potential hazards of ZNP exposure in patients with inflammatory dermatoses, reveals the mechanism of injury by which ZNPs induce skin toxicity, and provides data for future dermatotoxicological studies on ZNPs.