Dai Tianming, Xue Xiang, Huang Jian, Yang Zhenyu, Xu Pengfei, Wang Min, Xu Wuyan, Feng Zhencheng, Zhu Weicong, Xu Yangyang, Chen Junyan, Li Siming, Meng Qingqi
Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China.
Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China.
Cell Death Discov. 2023 Jul 8;9(1):234. doi: 10.1038/s41420-023-01522-x.
Sterol carrier protein 2 (SCP2) is highly expressed in human osteoarthritis (OA) cartilage, accompanied by ferroptosis hallmarks, especially the accumulation of lipid hydroperoxides (LPO). However, the role of SCP2 in chondrocyte ferroptosis remains unexplored. Here, we identify that SCP2 transports cytoplasmic LPO to mitochondria in RSL3-induced chondrocyte ferroptosis, resulting in mitochondrial membrane damage and release of reactive oxygen species (ROS). The localization of SCP2 on mitochondria is associated with mitochondrial membrane potential, but independent of microtubules transport or voltage-dependent anion channel. Moreover, SCP2 promotes lysosomal LPO increase and lysosomal membrane damage through elevating ROS. However, SCP2 is not directly involved in the cell membrane rupture caused by RSL3. Inhibition of SCP2 markedly protects mitochondria and reduces LPO levels, attenuating chondrocyte ferroptosis in vitro and alleviating the progression of OA in rats. Our study demonstrates that SCP2 mediates the transport of cytoplasmic LPO to mitochondria and the spread of intracellular LPO, accelerating chondrocyte ferroptosis.
固醇载体蛋白2（SCP2）在人类骨关节炎（OA）软骨中高表达，伴有铁死亡特征，尤其是脂质氢过氧化物（LPO）的积累。然而，SCP2在软骨细胞铁死亡中的作用仍未被探索。在此，我们发现SCP2在RSL3诱导的软骨细胞铁死亡中，将细胞质中的LPO转运至线粒体，导致线粒体膜损伤并释放活性氧（ROS）。SCP2在线粒体上的定位与线粒体膜电位相关，但与微管运输或电压依赖性阴离子通道无关。此外，SCP2通过升高ROS促进溶酶体LPO增加和溶酶体膜损伤。然而，SCP2并不直接参与RSL3引起的细胞膜破裂。抑制SCP2可显著保护线粒体并降低LPO水平，减轻体外软骨细胞铁死亡，并缓解大鼠OA的进展。我们的研究表明，SCP2介导细胞质LPO向线粒体的转运以及细胞内LPO的扩散，加速软骨细胞铁死亡。
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