Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.
Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.
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亲环蛋白 D 诱导的线粒体损伤导致小鼠脑出血后轴突损伤
DOI：
10.4103/1673-5374.353495
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发表时间：
2023-04
影响因子：
6.1
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Yang Y;Zhang KY;Chen XZ;Yang CY;Wang J;Lei XJ;Quan YL;Chen WX;Zhao HL;Yang LK;Wang YH;Chen YJ;Feng H
线粒体通透性转换孔是一种非特异性的跨膜通道。抑制线粒体通透性转换孔开放已被证明可以减轻线粒体肿胀、钙超载和轴突变性。亲环素D是线粒体通透性转换孔的重要成分。亲环素D是否参与脑出血后线粒体损伤和轴突损伤尚不清楚。本研究通过向Thy 1-YFP小鼠纹状体内注射自体血和氧合血红蛋白建立了脑出血小鼠模型，其中锥体神经元和轴突表达黄色荧光蛋白。我们还模拟脑出血在体外PC 12细胞使用氧合血红蛋白。我们发现脑出血早期轴突变性依赖于亲环素D激活引起的线粒体肿胀和线粒体通透性转换孔开放。我们进一步研究了亲环素D在脑出血小鼠模型和PC 12细胞模型中的作用机制。我们发现，环孢菌素A抑制和亲环素D的短发夹RNA干扰减少线粒体通透性转换孔开放和线粒体损伤。此外，亲环素D和线粒体通透性转换孔开放的抑制保护皮质脊髓束的完整性和减轻脑出血引起的运动功能障碍。我们的研究结果表明，亲环素D是脑出血后轴突变性的关键介质;抑制亲环素D的表达可以保护线粒体的结构和功能，并进一步减轻脑出血后皮质脊髓束损伤和运动功能障碍。我们的发现为预防中枢神经系统疾病中白色物质损伤的轴突变性和随后的功能障碍提供了一个治疗靶点。
The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.
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影响因子：
3.4
作者：
Chen ZR;Ma Y;Guo HH;Lu ZD;Jin QH
通讯作者：
Jin QH
DOI：
10.1523/jneurosci.4065-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
通讯作者：
Court FA
影响因子：
64.5
作者：
Chen B;Li Y;Yu B;Zhang Z;Brommer B;Williams PR;Liu Y;Hegarty SV;Zhou S;Zhu J;Guo H;Lu Y;Zhang Y;Gu X;He Z
通讯作者：
He Z
影响因子：
25
作者：
Guo L;Xiong H;Kim JI;Wu YW;Lalchandani RR;Cui Y;Shu Y;Xu T;Ding JB
通讯作者：
Ding JB
影响因子：
82.9
作者：
Du, Heng;Guo, Lan;Fang, Fang;Chen, Doris;Sosunov, Alexander A.;McKhann, Guy M.;Yan, Yilin;Wang, Chunyu;Zhang, Hong;Molkentin, Jeffery D.;Gunn-Moore, Frank J.;Vonsattel, Jean Paul;Arancio, Ottavio;Chen, John Xi;Du Yan, Shi
通讯作者：
Du Yan, Shi