Bone Research ( IF 14.3 ) Pub Date : 2024-03-29 , DOI: 10.1038/s41413-024-00317-9 Ziqian Xiang 1, 2 , Pengfei Zhang 1 , Chunwang Jia 1 , Rongkun Xu 1 , Dingren Cao 3 , Zhaoning Xu 4 , Tingting Lu 5 , Jingwei Liu 6 , Xiaoxiong Wang 1, 2 , Cheng Qiu 1 , Wenyang Fu 1 , Weiwei Li 7 , Lei Cheng 1 , Qiang Yang 8 , Shiqing Feng 1, 9 , Lianlei Wang 1 , Yunpeng Zhao 1 , Xinyu Liu 1
To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.
中文翻译:
Piezo1 通道通过介导机械应力诱导的铁流入加剧髓核细胞的铁死亡
迄今为止,已发现几种分子可以促进铁流入,但铁流入通道的类型仍有待阐明。在这里,Piezo1 通道被确定为响应机械应力的关键铁转运蛋白。 Piezo1 介导的铁过载扰乱了髓核细胞 (NPC) 中的铁代谢并加剧了铁死亡。重要的是,Piezo1 诱导的铁流入独立于转铁蛋白受体 (TFRC),而转铁蛋白受体是一种公认的铁守门人。此外,Piezo1 的药理失活可显着减少铁积累,减轻线粒体 ROS,并抑制机械应力刺激中的铁死亡改变。此外,条件性敲除Piezo1( Col2a1-CreERT Piezo1 flox/flox )可减轻机械损伤引起的椎间盘退变(IVDD)。值得注意的是,在Piezo1/Gpx4条件双敲除 (cDKO) 小鼠 ( Col2a1-CreERT Piezo1 flox/flox /Gpx4 flox/flox ) 中,IVDD 中 Piezo1 缺陷的保护作用受到削弱。这些发现表明 Piezo1 是铁流入的潜在决定因素,表明 Piezo1-铁-铁死亡轴可能为机械应力诱发疾病的治疗提供线索。