ISRIB improves white matter injury following TBI by inhibiting NCOA4-mediated ferritinophagy

作者全名：Zhou, Wenzhu; Liang, Yidan; Liao, Xinyu; Tong, Luyao; Du, Weihong; Fu, Wenqiao; Tian, Shanshan; Deng, Yongbing; Jiang, Xue

作者地址：[Zhou, Wenzhu; Liao, Xinyu; Jiang, Xue] Chongqing Med Univ, Coll Basic Med, Mol Med & Canc Res Ctr, Dept Biochem & Mol Biol, Chongqing 400016, Peoples R China; [Liang, Yidan; Tian, Shanshan; Deng, Yongbing] Chongqing Univ, Ctr Hosp, Dept Chongqing Emergency Med Ctr, Sch Med, Chongqing 400016, Peoples R China; [Tong, Luyao] Anhui Med Coll, Dept Med Technol, Hefei 230601, Peoples R China; [Du, Weihong] Capital Med Univ, Adv Innovat Ctr Human Brain Protect, Sch Basic Med Sci, Dept Histol & Embryol,Beijing Key Lab Canc Invas &, Beijing 100069, Peoples R China; [Fu, Wenqiao] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing 400016, Peoples R China

通信作者：Jiang, X (通讯作者)，Chongqing Med Univ, Coll Basic Med, Mol Med & Canc Res Ctr, Dept Biochem & Mol Biol, Chongqing 400016, Peoples R China.; Deng, YB (通讯作者)，Chongqing Univ, Ctr Hosp, Dept Chongqing Emergency Med Ctr, Sch Med, Chongqing 400016, Peoples R China.

来源：NEUROCHEMISTRY INTERNATIONAL

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001237124200001

JCR分区：Q1

影响因子：4.4

年份：2024

卷号：177

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Traumatic brain injury; White matter injury; Ferritinophagy; ISRIB; Ferroptosis

摘要：Traumatic brain injury (TBI) often results in persistent neurological dysfunction, which is closely associated with white matter injury. The mechanisms underlying white matter injury after TBI remain unclear. Ferritinophagy is a selective autophagic process that degrades ferritin and releases free iron, which may cause ferroptosis. Although ferroptosis has been demonstrated to be involved in TBI, it is unclear whether ferritinophagy triggers ferroptosis in TBI. Integrated stress response inhibitor (ISRIB) has neuroprotective properties. However, the effect of ISRIB on white matter after TBI remains uncertain. We aimed to investigate whether ferritinophagy was involved in white matter injury following TBI and whether ISRIB can mitigate white matter injury after TBI by inhibiting ferritinophagy. In this study, controlled cortical impact (CCI) was performed on rats to establish the TBI model. Ferritinophagy was measured by assessing the levels of nuclear receptor coactivator 4 (NCOA4), which regulates ferritinophagy, ferritin heavy chain 1(FTH1), LC3, ATG5, and FTH1 colocalization with LC3 in the white matter. Increased NCOA4 and decreased FTH1 were detected in our study. FTH1 colocalization with LC3 enhanced in the white matter after TBI, indicating that ferritinophagy was activated. Immunofluorescence co-localization results also suggested that ferritinophagy occurred in neurons and oligodendrocytes after TBI. Furthermore, ferroptosis was assessed by determining free iron content, MDA content, GSH content, and Perl ' s staining. The results showed that ferroptosis was suppressed by NCOA4 knockdown via shNCOA4 lentivirus infection, indicating that ferroptosis in TBI is triggered by ferritinophagy. Besides, NCOA4 deletion notably improved white matter injury following TBI, implying that ferritinophagy contributed to white matter injury. ISRIB treatment reduced the occurrence of ferritinophagy in neurons and oligodendrocytes, attenuated ferritinophagy-induced ferroptosis, and alleviated white matter injury. These findings suggest that NCOA4mediated ferritinophagy is a critical mechanism underlying white matter injury after TBI. ISRIB holds promise as a therapeutic agent for this condition.

基金机构：Natural Science Foundation Project of Chongqing Science and Technology Commission [cstc2020jcyj- msxm0769]; Science and Technology planning Project of Yuzhong District of Chongqing [20200135]; Chongqing University Medical -Industrial Integration Key Program [2023CDJYGRH-ZD06]

基金资助正文：This work was supported by the Natural Science Foundation Project of Chongqing Science and Technology Commission (Grant cstc2020jcyj- msxm0769 to Yongbing Deng) , the Science and Technology planning Project of Yuzhong District of Chongqing (Grant 20200135 to Yongbing Deng and Grant 20210171to Yidan Liang) , and the Chongqing Univer- sity Medical -Industrial Integration Key Program (Grant 2023CDJYGRH-ZD06) .