Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury.
Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury.
复制标题
DOI：
10.1038/s41419-022-05369-5
复制
发表时间：
2022-12-20
影响因子：
9
通讯作者：
Xu, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Liu, Nai-Kui;Deng, Ling-Xiao;Wang, Miao;Lu, Qing-Bo;Wang, Chunyan;Wu, Xiangbing;Wu, Wei;Wang, Ying;Qu, Wenrui;Han, Qi;Xia, Yongzhi;Ravenscraft, Baylen;Li, Jin-Lian;You, Si-Wei;Wipf, Peter;Han, Xianlin;Xu, Xiao-Ming
长期以来，磷脂的改变与脊髓损伤(SCI)有关。然而，它们在介导细胞死亡和组织修复中的具体作用和信号级联仍不清楚。在这里，我们研究了线粒体特异性磷脂家族心磷脂(CL)的改变是否在脊髓损伤后线粒体功能障碍和神经元死亡中发挥关键作用。采用脂质组学分析方法，对成年大鼠脊髓第10节段(T10)中度挫伤后脊髓CL的变化进行了研究。进行细胞、分子和遗传学评估，以确定CL改变是否介导了脊髓损伤后线粒体功能障碍和神经元死亡，如果是，逆转CL改变是否导致脊髓损伤后的神经保护。利用脂质组学分析，我们发现了脊髓损伤早期的CL改变。鉴定出50多种不同的CL物种，其中50%的物种在脊髓损伤后表现出显著的丰度下降。减少的CL物种主要含有易受过氧化影响的多不饱和脂肪酸。同时，脊髓损伤后脂质过氧化标志物4-HNE显著升高。我们发现，线粒体氧化应激不仅诱导CL氧化，而且通过激活cPLA2水解CL而导致CL丢失。CL改变导致线粒体功能障碍和神经元死亡。值得注意的是，XJB-5-131，一种新型的线粒体靶向电子和活性氧自由基清除剂，对CL改变的药物抑制，减少了成年大鼠脊髓损伤后的细胞死亡、组织损伤和运动障碍。提示CL改变可能是介导损伤后神经元死亡的一种新机制，是改善继发性脊髓损伤的潜在治疗靶点。
Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following a moderate contusive SCI at the 10th thoracic (T10) level. Cellular, molecular, and genetic assessments were performed to determine whether CL alterations mediate mitochondrial dysfunction and neuronal death after SCI, and, if so, whether reversing CL alteration leads to neuroprotection after SCI. Using lipidomic analysis, we uncovered CL alterations at an early stage of SCI. Over 50 distinct CL species were identified, of which 50% showed significantly decreased abundance after SCI. The decreased CL species contained mainly polyunsaturated fatty acids that are highly susceptible to peroxidation. In parallel, 4-HNE, a lipid peroxidation marker, significantly increased after SCI. We found that mitochondrial oxidative stress not only induced CL oxidation, but also resulted in CL loss by activating cPLA2 to hydrolyze CL. CL alterations induced mitochondrial dysfunction and neuronal death. Remarkably, pharmacologic inhibition of CL alterations with XJB-5-131, a novel mitochondria-targeted electron and reactive oxygen species scavenger, reduced cell death, tissue damage and ameliorated motor deficits after SCI in adult rats. These findings suggest that CL alteration could be a novel mechanism that mediates injury-induced neuronal death, and a potential therapeutic target for ameliorating secondary SCI.
登录
查看更多内容
影响因子：
82.9
作者：
Crowe, MJ;Bresnahan, JC;Beattie, MS
通讯作者：
Beattie, MS
影响因子：
2.9
作者：
Han, Xianlin;Yang, Jingyue;Gross, Richard W.
通讯作者：
Gross, Richard W.
影响因子：
14.8
作者：
Kagan, VE;Tyurin, VA;Borisenko, GG
通讯作者：
Borisenko, GG
影响因子：
4.2
作者：
Baker, KA;Hagg, T
通讯作者：
Hagg, T
影响因子：
4.2
作者：
Beattie, MS;Farooqui, AA;Bresnahan, JC
通讯作者：
Bresnahan, JC