The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more about our disclaimer.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2022 Jul; 36(7): 902–907.
PMCID: PMC9288914

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

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

Find articles by 鑫 缪

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

Find articles by 俊卿 林

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 Corresponding author.
郑宪友,Email: moc.621@uoynaixgnehz

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( 图1 )。

The role of various mechanisms of mitochondrial dysfunction in SCI and its relevant treatments

线粒体功能障碍各种机制在SCI中的作用及相关治疗

2.1. 线粒体能量代谢异常

线粒体功能障碍引起的能量代谢异常在SCI中扮演重要角色。线粒体基质中丙酮酸脱氢酶(pyruvate dehydrogenase,PDH)是线粒体呼吸过程中的关键酶 [ 12 ] 。SCI后,PDH活性明显被抑制,丙酮酸转化生成乙酰辅酶A过程受阻。乙酰辅酶A在三羧酸循环以及还原型烟酰胺腺嘌呤二核苷酸(reduced nicotinamide adenine dinucleotide,NADH)和还原型黄素腺嘌呤二核苷酸(reduced flavine adenine dinucleotide,FADH2)的生成中至关重要。NADH和FADH2在线粒体电子传递链中被氧化的同时为ATP合成提供电子,乙酰辅酶A生成受阻进一步引起ATP产生减少 [ 12 - 13 ] 。ATP的缺乏会导致由离子通道失活介导的兴奋性毒性、ROS形成以及炎症反应的激活 [ 13 ]

鉴于SCI后乙酰辅酶A产生减少,基于能量代谢途径治疗SCI需要引入一种可以作为能量来源的替代底物。乙酰左旋肉碱可以有效绕过PDH,通过线粒体中肉碱乙酰转移酶将乙酰基团转移至辅酶A形成乙酰辅酶A,增加乙酰辅酶A水平 [ 16 ] ,为三羧酸循环提供足够乙酰辅酶A以产生足够的NADH和FADH2,维持线粒体功能,改善SCI后的功能恢复,并保护脊髓内的白质和灰质免受进一步损伤 [ 17 ] ,可以作为急性SCI 后能量代谢的替代底物。虽然酮类、脂肪酸等其他底物也可以代谢成三羧酸循环的中间体,但这些物质能否作为替代能源底物尚未在SCI中得到验证。

2.2. 线粒体氧化应激异常

氧化应激是指生物体内氧化与抗氧化系统失衡,从而引起过多自由基累积的一种异常代谢状态 [ 3 ] 。SCI发生后,损伤区域处于缺血缺氧状态,线粒体功能障碍会导致自由基的产生超过超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽(glutathione,GSH)等内源性抗氧化剂的中和能力 [ 18 ] ,一方面引起脂质过氧化,严重损伤蛋白质和DNA,导致损伤部位神经纤维变性、脱髓鞘,甚至神经元凋亡 [ 19 ] ;另一方面容易扩散至损伤部位邻近区域,扩大损伤范围,加重继发性损伤 [ 20 ]

针对SCI后氧化应激所引起的过多自由基累积,可以通过外源性抗氧化剂干预或者增强内源性抗氧化能力来治疗SCI。α-生育酚可以清除脂质过氧自由基,改善氧化应激水平,促进SCI后运动和感觉功能恢复 [ 12 ] 。N-乙酰半胱氨酸酰胺是GSH前体N-乙酰半胱氨酸的一种含硫醇变体,可以提高GSH含量,改善线粒体功能障碍,促进SCI后大鼠运动感觉功能恢复 [ 17 ] 。体内外模型均发现GSK872 [受体相互作用蛋白激酶3(receptor interacting protein kinase 3,RIP3)特异性抑制剂] 能够抑制RIP3,调节GSH和SOD,改善线粒体抗氧化能力,进而改善运动功能以及脊髓水肿 [ 21 ] 。此外,阻断氧化应激相关信号通路传导也可以作为经氧化应激途径治疗SCI的一种思路。二甲双胍可以通过Akt/Nrf2/ARE信号通路,抑制过度氧化应激降低ROS水平,恢复线粒体功能,稳定微管,进而在SCI后起保护作用 [ 18 ]

2.3. 线粒体介导的凋亡异常

细胞凋亡是一种细胞程序性死亡,可发生在神经元、星形胶质细胞、少突胶质细胞和小胶质细胞中 [ 22 ] 。由线粒体功能障碍引起的线粒体介导的凋亡,是导致SCI后持续性细胞丢失的关键因素 [ 23 ] 。在线粒体介导的凋亡中,B细胞淋巴瘤2(B cell lymphoma 2,Bcl-2)蛋白通常位于线粒体外膜上,可封闭Bcl-2相关X蛋白(Bcl-2 associated X protein,Bax)形成的孔道,阻断细胞色素C释放,调控细胞凋亡 [ 24 ] 。SCI发生后,DNA损伤、缺血和氧化应激等刺激促进线粒体介导的凋亡启动,Bcl-2表达下降,细胞色素C从线粒体释放进入细胞质基质中 [ 25 ] ,结合凋亡蛋白酶激活因子1,随后结合半胱氨酸天冬氨酸蛋白酶9(cysteinyl aspartate specific proteinase 9,Caspase-9)前体形成凋亡小体,激活Caspase-9触发Caspase级联反应,最终导致细胞凋亡 [ 26 ]

针对SCI后线粒体介导的凋亡,可以通过靶向线粒体介导凋亡的上游通路来治疗SCI。MK801(又称地佐环平/地卓西平,是一种中枢神经系统/抗癫痫/脑保护/精神类药物)能靶向拮抗凋亡通路上游N-甲基-D-天冬氨酸受体,减少神经元凋亡,改善SCI后的运动功能 [ 25 ] 。山楂叶总黄酮可以促进Bcl-2表达,降低Bax表达水平,减少线粒体介导的凋亡,并发挥神经保护作用,促进SCI大鼠运动功能恢复 [ 27 ] 。此外,黄苓苷可以通过PI3K/Akt信号通路,来抑制SCI后的血脊髓屏障通透性并减少神经元凋亡 [ 28 ] ,表明线粒体介导的凋亡信号通路也可以作为SCI的潜在治疗靶点。

2.4. 线粒体自噬异常

线粒体自噬是通过自噬降解受损线粒体释放细胞中潜在的损伤蛋白过程,对线粒体质量以及细胞稳态的维持具有重要生理作用 [ 25 ] 。SCI发生后,线粒体功能障碍会引起MMP下降,抑制人第10号染色体缺失的磷酸酶和张力蛋白同源基因诱导的假定激酶1(phosphatase and tensin homolog deleted on chromosome ten gene-induced putative kinase 1,PINK1)进入线粒体内,导致PINK1不断聚集在线粒体外膜上,进而招募并激活Parkin(一种E3泛素连接酶)。活化的Parkin会进一步泛素化Nip3样蛋白X(Nip3-like protein X,NIX)等自噬相关受体,促进自噬体形成,介导线粒体自噬的发生,在SCI后神经元凋亡中起重要作用 [ 29 ]

多项研究结果表明,通过外加干预增强线粒体自噬可以改善线粒体功能,减轻神经元凋亡,有利于SCI修复 [ 30 ] 。桦木酸能够提高NIX、Parkin表达,恢复自噬通量激活线粒体自噬,清除聚集的ROS,显著促进SCI后的功能恢复 [ 31 ] 。Liu等 [ 32 ] 在脊髓缺血-再灌注损伤体内模型中发现,下调miRNA-124表达具有神经保护作用,这种保护作用被证明与诱导线粒体自噬有关。有研究显示,雷帕霉素在小鼠SCI模型中促进p62和Parkin向损伤线粒体易位增强线粒体自噬,同时抑制细胞凋亡,进而促进运动功能的恢复 [ 33 ] 。然而,目前关于线粒体功能障碍介导的线粒体自噬对于SCI后的修复作用尚存在一定争议,其自噬可能是SCI潜在的治疗靶点,但诱导线粒体自噬能否促进SCI修复有待进一步研究阐明。

2.5. 线粒体通透性转换异常

线粒体通透性转换是由于多种因素引起mPTP开放,导致线粒体内膜通透性急剧增加的现象 [ 34 ] 。SCI发生后,细胞质Ca 2+ 缓冲能力下降,大量Ca 2+ 通过谷氨酸受体进入细胞质,线粒体功能障碍会导致线粒体中Ca 2+ 累积,触发mPTP开放 [ 13 ] ,一方面引起MMP显著降低和质子梯度丢失,ATP产生减少,进而破坏细胞的正常代谢并最终导致细胞凋亡 [ 34 ] ;另一方面增加H 2 O和其他分子进入线粒体,导致线粒体基质在与细胞质基质平衡过程中不断膨胀,直至外膜破裂,Ca 2+ 、ROS和促凋亡蛋白(如细胞色素C)释放到细胞质基质促进细胞凋亡 [ 12 ]

通过抑制mPTP形成,阻断线粒体通透性转换,进而保护线粒体功能,可能对SCI的治疗有显著益处。免疫抑制剂环孢菌素A(cyclosporin,CsA)通过结合mPTP组成部分亲环蛋白D(cyclo-philin D,Cyp-D)抑制mPTP,进而抑制线粒体通透性转换,增强线粒体功能和减少中枢神经系统细胞凋亡 [ 31 ] 。然而,CsA在SCI中的神经保护作用仍然存在争议,同时考虑到CsA毒性作用大 [ 35 ] ,因此将其作为治疗剂不太理想。N-甲基异亮氨酸环孢菌素(N-methyl-isoleucine-cyclosporin,NIM811)是一种CsA衍生物,也通过结合Cyp-D抑制mPTP介导神经保护作用,并且毒性作用小,低剂量可显著改善运动恢复,而较高剂量可增加脊髓组织保留和反射性膀胱控制 [ 36 ] 。目前关于NIM811治疗SCI效果的研究有限,有待进一步研究。

2.6. 线粒体生物合成异常

线粒体生物合成是指具有功能的线粒体合成的一个动态过程 [ 37 - 38 ] 。Ca 2+ 和ATP水平是触发线粒体生物合成的主要因素,其机制主要是受到过氧化酶体增殖物激活受体γ共激活因子1α(peroxisome-proliferator-activated γ co-activator-1α,PGC-1α)/核呼吸因子1和2(nuclear respiration factors 1 and 2,NRF-1/2)/线粒体转录因子A(mitochondrial transcription factor A,TFAM)通路调控。SCI发生后,线粒体功能障碍会引起ATP减少以及细胞内Ca 2+ 水平增加,PGC-1α表达下降,PGC-1α/NRF-1/2/TFAM通路受到抑制,线粒体生物合成减少 [ 39 ] 。Hu等 [ 40 - 41 ] 发现大鼠SCI模型中PGC-1α表达下降,通过维持或者过表达PGC-1α 可减少神经元凋亡,改善大鼠运动功能恢复,表明SCI后通过增加PGC-1α表达和促进线粒体生物合成具有潜在的治疗获益。

线粒体生物合成的药理激活可以通过激活β2-肾上腺素能受体和5-羟色胺1F(5-hydroxytryptamine 1F,5-HT 1F )受体来启动。β2-肾上腺素能受体激动剂福莫特罗可以促进SCI大鼠模型线粒体生物合成,增加腓肠肌和受损脊髓的线粒体数量,显著改善SCI后运动功能的恢复,这种作用被证明与福莫特罗阻止SCI后PGC-1α表达减少相关 [ 42 - 43 ] 。5-HT 1F 受体激动剂 {"type":"entrez-nucleotide","attrs":{"text":"LY344864","term_id":"1257802930","term_text":"LY344864"}} LY344864 和lasmiditan也能够诱导SCI后线粒体生物合成,改善线粒体稳态、血脑屏障完整性和运动功能 [ 37 44 ] 。尽管目前仍然处于探索状态,但通过诱导线粒体生物合成减轻线粒体功能障碍以促进SCI恢复,可以作为未来药物开发的新思路。

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)

References

1. Fischer I, Dulin JN, Lane MA Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci. 2020; 21 (7):366–383. doi: 10.1038/s41583-020-0314-2. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
2. Bie F, Wang K, Xu T, et al The potential roles of circular RNAs as modulators in traumatic spinal cord injury. Biomed Pharmacother. 2021; 141 :111826. doi: 10.1016/j.biopha.2021.111826. doi: 10.1016/j.biopha.2021.111826. [ PubMed ] [ CrossRef ] [ Google Scholar ]
3. Lin J, Xiong Z, Gu J, et al Sirtuins: Potential therapeutic targets for defense against oxidative stress in spinal cord injury. Oxid Med Cell Longev. 2021; 2021 :7207692. doi: 10.1155/2021/7207692. doi: 10.1155/2021/7207692. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
4. Flack JA, Sharma KD, Xie JY Delving into the recent advancements of spinal cord injury treatment: a review of recent progress. Neural Regen Res. 2022; 17 (2):283–291. doi: 10.4103/1673-5374.317961. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
5. Quadri SA, Farooqui M, Ikram A, et al Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev. 2020; 43 (2):425–441. doi: 10.1007/s10143-018-1008-3. [ PubMed ] [ CrossRef ] [ Google Scholar ]
6. Jiang M, Bai M, Lei J, et al Mitochondrial dysfunction and the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2020; 319 (6):F1105–F1116. doi: 10.1152/ajprenal.00285.2020. [ PubMed ] [ CrossRef ] [ Google Scholar ]
7. Andrabi SS, Yang J, Gao Y, et al Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction. J Control Release. 2020; 317 :300–311. doi: 10.1016/j.jconrel.2019.12.001. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
8. Slater PG, Domínguez-Romero ME, Villarreal M, et al Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci. 2022; 79 (5):239. doi: 10.1007/s00018-022-04261-x. doi: 10.1007/s00018-022-04261-x. [ PubMed ] [ CrossRef ] [ Google Scholar ]
9. Fan B, Wei Z, Feng S Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res. 2022; 10 (1):35. doi: 10.1038/s41413-022-00199-9. doi: 10.1038/s41413-022-00199-9. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
10. Hou Y, Luan J, Huang T, et al Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice by reducing oxidative stress, apoptosis, and inflammatory response. J Neuroinflammation. 2021; 18 (1):216. doi: 10.1186/s12974-021-02248-2. doi: 10.1186/s12974-021-02248-2. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
11. Anjum A, Yazid MD, Fauzi Daud M, et al Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 2020; 21 (20):7533. doi: 10.3390/ijms21207533.. doi: 10.3390/ijms21207533. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
12. McEwen ML, Sullivan PG, Rabchevsky AG, et al Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics. 2011; 8 (2):168–179. doi: 10.1007/s13311-011-0031-7. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
13. Springer JE, Prajapati P, Sullivan PG Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury. Neural Regen Res. 2018; 13 (8):1338–1341. doi: 10.4103/1673-5374.235218. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
14. Baroncini A, Maffulli N, Eschweiler J, et al Pharmacological management of secondary spinal cord injury. Expert Opin Pharmacother. 2021; 22 (13):1793–1800. doi: 10.1080/14656566.2021.1918674. [ PubMed ] [ CrossRef ] [ Google Scholar ]
15. Scholpa NE, Schnellmann RG Mitochondrial-based therapeutics for the treatment of spinal cord injury: Mitochondrial biogenesis as a potential pharmacological target. J Pharmacol Exp Ther. 2017; 363 (3):303–313. doi: 10.1124/jpet.117.244806. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
16. Patel SP, Sullivan PG, Lyttle TS, et al Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. Neuroscience. 2012; 210 :296–307. doi: 10.1016/j.neuroscience.2012.03.006. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
17. Patel SP, Sullivan PG, Pandya JD, et al N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol. 2014; 257 :95–105. doi: 10.1016/j.expneurol.2014.04.026. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
18. Wang H, Zheng Z, Han W, et al Metformin promotes axon regeneration after spinal cord injury through inhibiting oxidative stress and stabilizing microtubule. Oxid Med Cell Longev. 2020; 2020 :9741369. doi: 10.1155/2020/9741369. doi: 10.1155/2020/9741369. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
19. Kim JW, Mahapatra C, Hong JY, et al Functional recovery of contused spinal cord in rat with the injection of optimal-dosed cerium oxide nanoparticles. Adv Sci (Weinh) 2017; 4 (10):1700034. doi: 10.1002/advs.201700034. doi: 10.1002/advs.201700034. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
20. Luo W, Wang Y, Lin F, et al Selenium-doped carbon quantum dots efficiently ameliorate secondary spinal cord injury via scavenging reactive oxygen species. Int J Nanomedicine. 2020; 15 :10113–10125. doi: 10.2147/IJN.S282985. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
21. Wang Y, Jiao J, Zhang S, et al RIP3 inhibition protects locomotion function through ameliorating mitochondrial antioxidative capacity after spinal cord injury. Biomed Pharmacother. 2019; 116 :109019. doi: 10.1016/j.biopha.2019.109019. doi: 10.1016/j.biopha.2019.109019. [ PubMed ] [ CrossRef ] [ Google Scholar ]
22. Shi Z, Yuan S, Shi L, et al Programmed cell death in spinal cord injury pathogenesis and therapy. Cell Prolif. 2021; 54 (3):e12992. doi: doi: 10.1111/cpr.12992. doi: 10.1111/cpr.12992. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
23. Ying Y, Zhang Y, Tu Y, et al Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis. Front Cell Dev Biol. 2021; 9 :693694. doi: 10.3389/fcell.2021.693694. doi: 10.3389/fcell.2021.693694. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
24. Bock FJ, Tait SWG Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020; 21 (2):85–100. doi: 10.1038/s41580-019-0173-8. [ PubMed ] [ CrossRef ] [ Google Scholar ]
25. Rabchevsky AG, Michael FM, Patel SP Mitochondria focused neurotherapeutics for spinal cord injury. Exp Neurol. 2020; 330 :113332. doi: doi: 10.1016/j.expneurol.2020.113332. doi: 10.1016/j.expneurol.2020.113332. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
26. Abbaszadeh F, Fakhri S, Khan H Targeting apoptosis and autophagy following spinal cord injury: Therapeutic approaches to polyphenols and candidate phytochemicals. Pharmacol Res. 2020; 160 :105069. doi: 10.1016/j.phrs.2020.105069. doi: 10.1016/j.phrs.2020.105069. [ PubMed ] [ CrossRef ] [ Google Scholar ]
27. Zhang Q, Xiong Y, Li B, et al Total flavonoids of hawthorn leaves promote motor function recovery via inhibition of apoptosis after spinal cord injury. Neural Regen Res. 2021; 16 (2):350–356. doi: 10.4103/1673-5374.286975. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
28. Zhao R, Wu X, Bi XY, et al Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury. Neural Regen Res. 2022; 17 (5):1080–1087. doi: 10.4103/1673-5374.324857. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
29. Zhu M, Huang X, Shan H, et al Mitophagy in traumatic brain injury: A New target for therapeutic intervention. Oxid Med Cell Longev. 2022; 2022 :4906434. doi: 10.1155/2022/4906434. doi: 10.1155/2022/4906434. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
30. Mao Y, Du J, Chen X, et al Maltol promotes mitophagy and inhibits oxidative stress via the nrf2/pink1/parkin pathway after spinal cord injury. Oxid Med Cell Longev. 2022; 2022 :1337630. doi: 10.1155/2022/1337630. doi: 10.1155/2022/1337630. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
31. Kim SY, Shim MS, Kim KY, et al Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis. 2014; 5 (3):e1105. doi: 10.1038/cddis.2014.80. doi: 10.1038/cddis.2014.80. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
32. Liu K, Yan L, Jiang X, et al Acquired inhibition of microRNA-124 protects against spinal cord ischemia-reperfusion injury partially through a mitophagy-dependent pathway. J Thorac Cardiovasc Surg. 2017; 154 (5):1498–1508. doi: 10.1016/j.jtcvs.2017.05.046. [ PubMed ] [ CrossRef ] [ Google Scholar ]
33. Li Q, Gao S, Kang Z, et al Rapamycin enhances mitophagy and attenuates apoptosis after spinal ischemia-reperfusion injury. Front Neurosci. 2018; 12 :865. doi: 10.3389/fnins.2018.00865. doi: 10.3389/fnins.2018.00865. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
34. Neginskaya MA, Pavlov EV, Sheu SS Electrophysiological properties of the mitochondrial permeability transition pores: Channel diversity and disease implication. Biochim Biophys Acta Bioenerg. 2021; 1862 (3):148357. doi: 10.1016/j.bbabio.2020.148357. doi: 10.1016/j.bbabio.2020.148357. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
35. Wang S, Smith GM, Selzer ME, et al Emerging molecular therapeutic targets for spinal cord injury. Expert Opin Ther Targets. 2019; 23 (9):787–803. doi: 10.1080/14728222.2019.1661381. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
36. Springer JE, Visavadiya NP, Sullivan PG, et al Post-injury treatment with NIM811 promotes recovery of function in adult female rats after spinal cord contusion: A dose-response study. J Neurotrauma. 2018; 35 (3):492–499. doi: 10.1089/neu.2017.5167. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
37. Simmons EC, Scholpa NE, Schnellmann RG FDA-approved 5-HT 1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury . Exp Neurol. 2021; 341 :113720. doi: 10.1016/j.expneurol.2021.113720. doi: 10.1016/j.expneurol.2021.113720. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
38. Simmons EC, Scholpa NE, Schnellmann RG Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol. 2020; 329 :113309. doi: 10.1016/j.expneurol.2020.113309. doi: 10.1016/j.expneurol.2020.113309. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
39. Cardanho-Ramos C, Morais VA Mitochondrial biogenesis in neurons: How and where. Int J Mol Sci. 2021; 22 (23):13059. doi: 10.3390/ijms222313059. doi: 10.3390/ijms222313059. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
40. Hu J, Lang Y, Zhang T, et al Lentivirus-mediated PGC-1α overexpression protects against traumatic spinal cord injury in rats. Neuroscience. 2016; 328 :40–49. doi: 10.1016/j.neuroscience.2016.04.031. [ PubMed ] [ CrossRef ] [ Google Scholar ]
41. Hu J, Lang Y, Cao Y, et al The neuroprotective effect of tetramethylpyrazine against contusive spinal cord injury by activating PGC-1α in rats. Neurochem Res. 2015; 40 (7):1393–1401. doi: 10.1007/s11064-015-1606-1. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
42. Scholpa NE, Williams H, Wang W, et al Pharmacological stimulation of mitochondrial biogenesis using the food and drug administration-approved beta2-adrenoreceptor agonist formoterol for the treatment of spinal cord injury. J Neurotrauma. 2019; 36 (6):962–972. doi: 10.1089/neu.2018.5669. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
43. Scholpa NE, Simmons EC, Crossman JD, et al Time-to-treatment window and cross-sex potential of β 2 -adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury . Toxicol Appl Pharmacol. 2021; 411 :115366. doi: 10.1016/j.taap.2020.115366. doi: 10.1016/j.taap.2020.115366. [ PubMed ] [ CrossRef ] [ Google Scholar ]
44. Simmons EC, Scholpa NE, Cleveland KH, et al 5-hydroxytryptamine 1F receptor agonist induces mitochondrial biogenesis and promotes recovery from spinal cord injury. J Pharmacol Exp Ther. 2020; 372 (2):216–223. doi: 10.1124/jpet.119.262410. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Articles from Chinese Journal of Reparative and Reconstructive Surgery are provided here courtesy of Sichuan University