Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.
Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.
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DOI：
10.1111/jnc.13008
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发表时间：
2015-02
影响因子：
4.7
通讯作者：
Simpkins JW
中科院分区：
文献类型：
--
作者：
Doll DN;Rellick SL;Barr TL;Ren X;Simpkins JW
已知肿瘤坏死因子α（TNF-α）可加重缺血性脑损伤;然而，其机制尚不清楚。先前的研究评估了TNF-α对长期暴露于高剂量TNF-α的神经元的影响，这与病理生理学无关。我们使用病理生理学相关的卒中后TNF-α浓度来表征TNF-α对基础呼吸、ATP产生和最大呼吸的快速作用。我们观察到早在暴露于低剂量TNF-α后1.5 h，HT-22细胞和原代神经元中的线粒体功能就降低，随后细胞活力降低。随后，我们使用HT-22细胞系来确定TNF-α引起线粒体功能快速和深刻降低的机制。用TNF-R1抗体而不是TNF-R2抗体预处理，减轻了TNF-α的神经毒性作用，表明TNF-α通过TNF-R1发挥其神经毒性作用。我们观察到暴露于TNF-α后caspase 8活性增加，线粒体膜电位降低，导致细胞色素c从线粒体释放到胞质溶胶中。这些新发现首次表明，急性暴露于病理生理相关浓度的TNF-α具有通过线粒体功能快速受损介导的神经毒性作用。
Tumor necrosis factor alpha (TNF-α) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-α on neurons with long exposures to high doses of TNF-α, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-α on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, post-stroke concentrations of TNF-α. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-α, followed by a decrease in cell viability in HT-22 cells and primary neurons. Subsequently, we used the HT-22 cell line to determine the mechanism by which TNF-α causes a rapid and profound reduction in mitochondrial function. Pre-treating with TNF-R1 antibody, but not TNF-R2 antibody, ameliorated the neurotoxic effects of TNF-α, indicating that TNF-α exerts its neurotoxic effects through TNF-R1. We observed an increase in caspase 8 activity and a decrease in mitochondrial membrane potential after exposure to TNF-α which resulted in a release of cytochrome c from the mitochondria into the cytosol. These novel findings indicate for the first time that an acute exposure to pathophysiologically relevant concentrations of TNF-α has neurotoxic effects mediated by a rapid impairment of mitochondrial function.
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影响因子：
1.7
作者：
Nayak AR;Kashyap RS;Kabra D;Purohit HJ;Taori GM;Daginawala HF
通讯作者：
Daginawala HF
影响因子：
8.3
作者：
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Chamorro, A
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16.2
作者：
CHENG, B;CHRISTAKOS, S;MATTSON, MP
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MATTSON, MP
影响因子：
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作者：
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Seishima, M
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8.3
作者：
LIU, T;CLARK, RK;FEUERSTEIN, GZ
通讯作者：
FEUERSTEIN, GZ