脊髓
脊髓损伤
程序性细胞死亡
细胞生物学
体内
活性氧
细胞凋亡
二氢月桂酸脱氢酶
线粒体
化学
生物
神经科学
生物化学
酶
生物技术
作者
Dachuan Li,Xiao Lu,Guangyu Xu,Siyang Liu,Zhaoyang Gong,Feizhou Lu,Xinlei Xia,Jianyuan Jiang,Hongli Wang,Fei Zou,Xiaosheng Ma
摘要
Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non-apoptotic type of cell death that has only recently been identified, which is marked primarily by iron-dependent and lipid-derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous.In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin-induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro.First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis-related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53.Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.
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