Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury
Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury
复制标题
DOI：
10.1016/j.mito.2015.11.001
复制
发表时间：
2016-01-01
期刊：
影响因子：
4.4
通讯作者：
Margulies, Susan S.
中科院分区：
文献类型：
--
作者：
Kilbaugh, Todd J.;Karlsson, Michael;Margulies, Susan S.
创伤性脑损伤（TBI）是一个重要的健康问题，也是全球儿童死亡的主要原因。线粒体功能障碍是继发性TBI级联反应的关键组成部分。尽管有证据表明发育中大脑的反应与成人不同，尤其是在弥漫性非冲击性TBI中，但儿科大脑中的线粒体反应的研究有限。我们在弥漫性TBI（快速非冲击旋转损伤：RNR）的猪模型中使用高分辨率呼吸测定法对线粒体生物能量学进行了详细的评估，并检查了皮质和海马。底物-解偶联剂-底物-滴定方案检查了各个复合物的作用以及解偶联的最大呼吸。每毫克组织的呼吸也与柠檬酸合酶活性（CS）有关，试图控制损伤后线粒体含量的变化。弥散RNR刺激增加复合物II驱动的呼吸相对于海马中的线粒体含量相比，假。与假手术动物相比，两个区域的LEAK（状态40）呼吸增加，通过复合物I和II的会聚氧化磷酸化的呼吸比率降低，表明氧化磷酸化在24 h时解偶联。该研究表明，在RNR后海马中，复合物I对会聚线粒体呼吸的贡献比例降低，同时复合物II驱动的呼吸增加。弥漫性TBI后24小时的线粒体呼吸因脑内位置而异。我们的结论是，通过复合物I和复合物II驱动的呼吸，氧化磷酸化的显著解偶联和会聚呼吸的改变揭示了受伤的高危儿童大脑的治疗机会。(C)2015 Elsevier B. V.和线粒体研究学会。All rights reserved.
Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. Mitochondrial response in the pediatric brain has limited investigation, despite evidence that the developing brain's response differs from that of the adult, especially in diffuse non-impact TBI. We performed a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 40) respiration increased in both regions, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24 h. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. Mitochondrial respiration 24 h after diffuse TBI varies by location within the brain. We concluded that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain. (C) 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.