Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice.
Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice.
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DOI：
10.1038/pr.2017.277
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发表时间：
2018-03
影响因子：
3.6
通讯作者：
Ten VS
中科院分区：
文献类型：
--
作者：
Sahni PV;Zhang J;Sosunov S;Galkin A;Niatsetskaya Z;Starkov A;Brookes PS;Ten VS
琥珀酸氧化驱动的反向电子传递(RET)被认为是缺血后线粒体加速产生活性氧(ROS)的机制。然而，目前尚不清楚再灌注后线粒体是否优先氧化琥珀酸化。新生小鼠采用莱斯-万努奇缺氧缺血性脑损伤(HI)模型，观察缺血脑内Krebs循环代谢产物、线粒体底物偏好和H_2O_2产生率。对照组小鼠脑线粒体呈现鱼藤酮敏感的Complex-I依赖呼吸，而HI-脑线粒体在再灌流开始时表现出Complex-II依赖的呼吸，因为鱼藤酮对呼吸的影响最小，但Complex-II的抑制使呼吸停止。这与HI小鼠大脑琥珀酸浓度增加30倍和过氧化氢释放率显著增加有关。再灌流60min时，脑组织琥珀酸含量和线粒体对鱼藤酮的反应与对照组无差异。这些数据是第一个体外证据，即在再灌流开始时，脑线粒体的代谢暂时从依赖复合体I的NADH氧化转变为复合体II连接的琥珀酸氧化。我们的研究为RET依赖的再灌流中ROS产生增加的机制的存在提供了关键支持。
Reverse electron transport (RET) driven by the oxidation of succinate has been proposed as the mechanism of accelerated production of reactive oxygen species (ROS) in post-ischemic mitochondria. However, it remains unclear whether upon reperfusion, mitochondria preferentially oxidase succinate. Neonatal mice were subjected to Rice-Vannucci model of hypoxicischemic brain injury (HI) followed by assessment of Krebs cycle metabolites, mitochondrial substrate preference, and H2O2 generation rate in the ischemic brain. While brain mitochondria from control mice exhibited a rotenonesensitive complex-I-dependent respiration, HI-brain mitochondria, at the initiation of reperfusion, demonstrated complex-II-dependent respiration, as rotenone minimally affected, but inhibition of complex-II ceased respiration. This was associated with a 30-fold increase of cerebral succinate concentration and significantly elevated H2O2 emission rate in HI-mice compared to controls. At sixty minutes of reperfusion, cerebral succinate content and the mitochondrial response to rotenone did not differ from that in controls. These data are the first ex-vivo evidence, that at the initiation of reperfusion, brain mitochondria transiently shift their metabolism from complex-I-dependent oxidation of NADH toward complex II-linked oxidation of succinate. Our study provides a critical piece of support for existence of the RET-dependent mechanism of elevated ROS production in reperfusion.
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影响因子：
8.3
作者：
Ten, VS;Wu, EX;Pinsky, DJ
通讯作者：
Pinsky, DJ
发育中的大脑中缺氧 - 缺血性损伤：起源于线粒体的活性氧的作用。
影响因子：
1.5
作者：
Ten VS;Starkov A
通讯作者：
Starkov A
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：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
8.3
作者：
Piantadosi, CA;Zhang, J
通讯作者：
Zhang, J