Yu Li,Min Yu,Junping Ren,Tianming Qiu,Jingyuan Zhang,Chenbing Wu,Jie Bai,Xiance Sun,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS), classified as a persistent organic pollutant, promotes mitochondrial iron overload through voltage-dependent anion channel 2 (VDAC2). However, the source of iron transported through VDAC2 remains unclear. Here, we reported that PFOS enhanced extracellular iron influx into human hepatocytes HepG2, which peaked at 6 h. Under PFOS exposure, total VDAC2 protein levels remained unchanged, whereas its expression increased in mitochondrial lysates but decreased in cytoplasmic lysates, which were observed both in HepG2 cells and mice liver. Meanwhile, the total protein expression of the extracellular iron importer ZRT/IRT-like protein 14 (ZIP14) was upregulated, whereas absent from the mitochondrial lysates. Knockdown of either VDAC2 or ZIP14 inhibited PFOS-induced extracellular iron influx and mitochondrial iron overload, but did not affect cytoplasmic iron levels. Notably, immunofluorescence colocalization analysis revealed that the timeline of mitochondrial redistribution toward the plasma membrane closely paralleled the course of increased extracellular iron influx. Furthermore, the result of molecular docking suggested the potential interaction between VDAC2 and ZIP14. Together, these works pointed out and further advanced our understanding of the extracellular iron transport into mitochondria in hepatocytes under PFOS exposure and revealed a potential therapeutic target for mitigating the disease mediated by iron-related mechanism.
Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5–24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
危险品化学品经营许可证（带存储）