Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis.
Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis.
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DOI：
10.1016/j.taap.2012.04.030
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发表时间：
2012-07-15
影响因子：
3.8
通讯作者：
Zhu, Bao Ting
中科院分区：
文献类型：
--
作者：
Fukui, Masayuki;Choi, Hye Joung;Zhu, Bao Ting
关键词：
近年来的研究表明，过量的线粒体超氧化物产生是神经退行性疾病的重要病因，由细胞脂质、蛋白质和核酸的氧化修饰引起。因此，了解线粒体氧化应激导致神经元死亡的机制是很重要的。本研究以培养的永生化小鼠海马神经元细胞（HT22）为模型，将其暴露于甲萘醌（也称为维生素K3）中以增加细胞内超氧化物的产生。我们发现甲萘醌在这些细胞的线粒体中引起超氧化物的优先积累，同时线粒体功能障碍和细胞ATP消耗迅速发展。甲萘醌诱导的神经元死亡不依赖于MAPK信号通路和半胱天冬酶的激活。半胱天冬酶缺乏激活是由于细胞ATP的快速消耗。观察到两种atp无关的线粒体核酸酶，即AIF和Endo G，在甲萘醌暴露后释放。使用特定sirna沉默它们的表达可导致线粒体超氧化物诱导的神经元死亡的短暂抑制（约12小时）。虽然抑制线粒体超氧化物歧化酶的表达可使神经元细胞对线粒体超氧化物诱导的细胞毒性显着敏感，但其过表达可提供强大的保护。总的来说，这些发现表明，与线粒体超氧化物诱导的细胞死亡相关的许多观察到的特征，包括半胱天冬酶依赖性、ATP水平的快速消耗、线粒体AIF和Endo G的释放以及线粒体肿胀，与细胞凋亡明显不同；相反，它们类似于一些已知的坏死性下垂的特征。
Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K3) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ~12 h) of mitochondrial superoxide-induced neuronal death. While suppression of the mitochondrial superoxide dismutase expression markedly sensitizes neuronal cells to mitochondrial superoxide-induced cytotoxicity, its over-expression confers strong protection. Collectively, these findings showed that many of the observed features associated with mitochondrial superoxide-induced cell death, including caspase independency, rapid depletion of ATP level, mitochondrial release of AIF and Endo G, and mitochondrial swelling, are distinctly different from those of apoptosis; instead they resemble some of the known features of necroptosis.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
15.9
作者：
Banerjee, Rebecca;Beal, M. Flint;Thomas, Bobby
通讯作者：
Thomas, Bobby
影响因子：
4.8
作者：
Connor, KM;Subbaram, S;Melendez, JA
通讯作者：
Melendez, JA
DOI：
10.1016/0005-2728(70)90220-3
发表时间：
1970-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
IYANAGI, T;YAMAZAKI, I
通讯作者：
YAMAZAKI, I
影响因子：
4.8
作者：
Kudin, AP;Bimpong-Buta, NYB;Kunz, WS
通讯作者：
Kunz, WS