SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis

Tianming Dai; Xiang Xue; Jian Huang; Zhenyu Yang; Pengfei Xu; Min Wang; Wuyan Xu; Zhencheng Feng; Weicong Zhu; Yangyang Xu; Junyan Chen; Siming Li; Qingqi Meng

doi:10.1038/s41420-023-01522-x

SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis

Cell Death Discov. 2023 Jul 8;9(1):234. doi: 10.1038/s41420-023-01522-x.

Authors

Tianming Dai^#¹, Xiang Xue^#², Jian Huang^#², Zhenyu Yang^#², Pengfei Xu³, Min Wang², Wuyan Xu², Zhencheng Feng², Weicong Zhu¹, Yangyang Xu⁴, Junyan Chen⁴, Siming Li⁵, Qingqi Meng⁶

Affiliations

¹ Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China.
² Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China.
³ Department of Thoracic and Vascular Surgery, University Hospital Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
⁴ Guizhou Medical University, Guiyang, 550025, China.
⁵ Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China. drsmli@163.com.
⁶ Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, China. mengqingqi@jnu.edu.cn.

^# Contributed equally.

Abstract

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.