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Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi.
2022 Jul; 36(7): 902–907.
Language:
Chinese
|
English
线粒体功能障碍在脊髓损伤中的作用及相关治疗研究进展
Advances of the role of mitochondrial dysfunction in the spinal cord injury and its relevant treatments
,
,
and
*
鑫 缪
上海交通大学附属第六人民医院骨科(上海 200233),
Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China
俊卿 林
上海交通大学附属第六人民医院骨科(上海 200233),
Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China
宪友 郑
上海交通大学附属第六人民医院骨科(上海 200233),
Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China
上海交通大学附属第六人民医院骨科(上海 200233),
Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China
Corresponding author.
1. SCI后线粒体的功能改变
SCI的病理过程包括原发性损伤和继发性损伤两个阶段
[
9
]
。原发性损伤主要是脊髓瞬间受到机械外力打击,神经元和胶质细胞受损,微血管遭到破坏
[
10
]
。而继发性损伤是在原发性损伤基础上发生一系列级联反应,最终导致神经元死亡、炎症、胶质瘢痕形成和线粒体功能障碍等改变
[
11
]
。其中,线粒体功能障碍被认为是影响SCI后功能障碍的重要原因。在SCI继发性损伤阶段,缺血、灌注不足造成损伤区域缺乏充足的氧气和葡萄糖供应,引起线粒体电子传递链破坏,导致线粒体功能受损,进而一方面引起线粒体ATP合成减少,另一方面引起电子从传递链中泄漏,与线粒体基质中的O
2
结合形成ROS,超过内源性抗氧化系统处理能力,加重SCI
[
12
]
。此外,SCI后机械介导的去极化和电压依赖性离子通道的开放引起细胞外兴奋性神经递质谷氨酸释放增加,进而过度激活谷氨酸受体,引起兴奋性毒性
[
5
]
。谷氨酸受体的过度激活使得大量Ca
2+
涌入神经元,增加Ca
2+
膜通透性,激活磷脂酶,诱发线粒体功能障碍
[
8
]
,进而导致细胞质基质和线粒体内Ca
2+
不断累积,触发线粒体通透性转换孔(mitochondrial permeability transition pore,mPTP)开放
[
13
]
。mPTP 的开放一方面会引起线粒体膜电位(mitochondrial membrane potential,MMP)显著降低抑制ATP的合成,另一方面允许H
2
O和其他分子进入线粒体,导致线粒体膨胀直至外膜破裂,释放线粒体内累积的Ca
2+
、ROS和促凋亡蛋白(如细胞色素C)进入细胞质基质,促进细胞死亡
[
14
]
。综上,SCI发生后,缺血、兴奋性毒性、Ca
2+
超载均会引起线粒体功能障碍,进而导致ATP减少、ROS产生增加、mPTP开放,进一步促进SCI发展。
2. 线粒体功能障碍在SCI中的作用及相关治疗
线粒体功能障碍会引起ATP生成不足、ATP依赖性离子泵失活以及兴奋性神经递质谷氨酸重吸收,最终导致兴奋性毒性、Ca
2+
超载,触发细胞死亡级联反应
[
15
]
。线粒体功能障碍主要表现在线粒体能量代谢、线粒体氧化应激、线粒体介导的凋亡、线粒体自噬、线粒体通透性转换以及线粒体生物合成等方面异常。SCI后继发性损伤阶段增强线粒体功能是一种潜在的治疗策略,以下将围绕线粒体功能障碍各种机制在SCI中的作用及相关治疗做一总结(
)。
3. 小结与展望
线粒体功能障碍是SCI继发性损伤阶段的重要特点,涉及线粒体能量代谢、线粒体氧化应激、线粒体介导的凋亡、线粒体自噬、线粒体通透性转换以及线粒体生物合成等方面异常,在SCI发展中起着重要作用。其中,线粒体能量代谢、线粒体氧化应激和线粒体通透性转换异常同时也是引起线粒体自噬异常、线粒体介导的凋亡和线粒体生物合成障碍的重要原因,及时纠正线粒体能量代谢异常、抑制线粒体氧化应激以及线粒体通透性转换,可能是比较关键的线粒体功能保护策略。
多种通过增强线粒体功能的药物经研究证明治疗SCI有效,但目前研究主要局限于SCI动物模型,这些药物对人体SCI是否有效以及药物的用量和安全性,还需要更多基础研究和临床试验验证。此外,SCI病理过程复杂涉及多种机制,单一增强线粒体功能的治疗策略可能无法在SCI后提供全面保护,可能需要联合多靶点治疗,比如增强线粒体功能的药物与抗炎药物联合使用。因此需要更详细地了解两者作用靶点以及它们之间的相互作用,以确定更为安全有效的治疗方式。
利益冲突 在课题研究和文章撰写过程中不存在利益冲突
作者贡献声明 缪鑫:文献查阅、文章撰写;林俊卿:资料分析、文章修改;郑宪友:选题设计、文章审核
Funding Statement
国家自然科学基金资助项目(81974331、82172421)
Funding Statement
National Natural Science Foundation of China (81974331, 82172421)
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