Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury.
Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury.
复制标题
通过靶向新生儿缺氧 - 缺血性脑损伤中的线粒体复合物I，氧化损伤的衰减。
DOI：
10.1016/j.freeradbiomed.2018.06.040
复制
发表时间：
2018-08-20
影响因子：
7.4
通讯作者：
Ten VS
中科院分区：
文献类型：
--
作者：
Kim M;Stepanova A;Niatsetskaya Z;Sosunov S;Arndt S;Murphy MP;Galkin A;Ten VS
建立持续的复氧/再灌注不仅确保了恢复，而且可能引发氧化应激起主要作用的再灌注损伤。这项研究提供了机制和这种机制特异性的治疗策略，以防止与再灌注驱动的线粒体代谢恢复相关的活性氧（ROS）的过度释放。在新生小鼠脑缺氧缺血（HI）和再灌注，我们研究了构象变化和活性的线粒体复合物I与和没有后HI管理的S-亚硝基化剂，MitoSNO。线粒体ROS产生、氧化性脑损伤、神经病理学和神经功能结果的评估用于定义MitoSNO的神经保护强度。体外研究了再灌注驱动的线粒体ROS产生对复合物I构象变化的特异性。HI使络合物I失活，将其构象从活性形式（A）改变为催化休眠的失活形式（D）。再灌注迅速将D型转化为A型，并增加ROS的产生。在再灌注开始时给予MitoSNO，减慢复合物I的D→A转变，减弱氧化应激，并显著改善神经恢复。在培养的神经元中，模拟缺血再灌注损伤后，MitoSNO显着减少ROS的产生和神经元死亡率。在缺氧-复氧的线粒体中，MitoSNO限制了D→A转换过程中ROS的释放。对再灌注反应的快速D→A构象再激活复合物I。这不仅对代谢恢复至关重要，而且有助于线粒体ROS的过度释放和再灌注损伤。我们建议，再灌注的开始应遵循药理学控制的复合物I的逐渐重新激活。
Establishing sustained reoxygenation/reperfusion ensures not only the recovery, but may initiate a reperfusion injury in which oxidative stress plays a major role. This study offers the mechanism and this mechanism-specific therapeutic strategy against excessive release of reactive oxygen species (ROS) associated with reperfusion-driven recovery of mitochondrial metabolism. In neonatal mice subjected to cerebral hypoxia-ischaemia (HI) and reperfusion, we examined conformational changes and activity of mitochondrial complex I with and without post-HI administration of S-nitrosating agent, MitoSNO. Assessment of mitochondrial ROS production, oxidative brain damage, neuropathological and neurofunctional outcomes were used to define neuroprotective strength of MitoSNO. A specificity of reperfusion-driven mitochondrial ROS production to conformational changes in complex I was examined in-vitro. HI deactivated complex I, changing its conformation from active form (A) into the catalytically dormant, de-active form (D). Reperfusion rapidly converted the D-form into the A-form and increased ROS generation. Administration of MitoSNO at the onset of reperfusion, decelerated D→A transition of complex I, attenuated oxidative stress, and significantly improved neurological recovery. In cultured neurons, after simulated ischaemia-reperfusion injury, MitoSNO significantly reduced ROS generation and neuronal mortality. In isolated mitochondria subjected to anoxia-reoxygenation, MitoSNO restricted ROS release during D→A transitions. Rapid D→A conformation in response to reperfusion reactivates complex I. This is essential not only for metabolic recovery, but also contributes to excessive release of mitochondrial ROS and reperfusion injury. We propose that the initiation of reperfusion should be followed by pharmacologically-controlled gradual reactivation of complex I.
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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：
4.3
作者：
Babot, Marion;Birch, Amanda;Labarbuta, Paola;Galkin, Alexander
通讯作者：
Galkin, Alexander
DOI：
10.1016/s0165-3806(00)00110-3
发表时间：
2000-12-29
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Puka-Sundvall, M;Gajkowska, B;Hagberg, H
通讯作者：
Hagberg, H
DOI：
10.1523/jneurosci.6303-11.2012
发表时间：
2012-02-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Niatsetskaya ZV;Sosunov SA;Matsiukevich D;Utkina-Sosunova IV;Ratner VI;Starkov AA;Ten VS
通讯作者：
Ten VS
影响因子：
6.6
作者：
Gorenkova, Natalia;Robinson, Emma;Galkin, Alexander
通讯作者：
Galkin, Alexander