Kilbaugh Todd J, Karlsson Michael, Duhaime Ann-Christine, Hansson Magnus J, Elmer Eskil, Margulies Susan S
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, SE-221 84 Lund, Sweden.
Mitochondrion. 2016 Jan;26:19-25. doi: 10.1016/j.mito.2015.11.001. Epub 2015 Nov 5.
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 4o) 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 24h. 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 24h 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.
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的大脑的反应与成人大脑不同，尤其是在弥漫性非撞击性TBI中，但对小儿大脑中线粒体反应的研究有限。我们使用高分辨率呼吸测定法在弥漫性TBI猪模型（快速非撞击性旋转损伤：RNR）中对线粒体生物能量学进行了详细评估，并检查了皮质和海马体。底物-解偶联剂-抑制剂滴定方案研究了各个复合体的作用以及解偶联的最大呼吸作用。每毫克组织的呼吸作用也与柠檬酸合酶活性（CS）相关，以此来控制损伤后线粒体含量的变异性。与假手术组相比，弥漫性RNR刺激海马体中复合体II驱动的呼吸作用相对于线粒体含量增加。与假手术动物相比，两个区域的LEAK（状态4o）呼吸作用均增加，通过复合体I和II的收敛性氧化磷酸化的呼吸比率降低，表明在24小时时氧化磷酸化解偶联。该研究表明，成比例地，RNR后海马体中复合体I对收敛性线粒体呼吸的贡献降低，同时复合体II驱动的呼吸作用增加。弥漫性TBI后24小时的线粒体呼吸作用因脑内位置而异。我们得出结论，氧化磷酸化的显著解偶联以及通过复合体I和复合体II驱动的呼吸作用在收敛性呼吸方面的改变揭示了受伤的高危小儿大脑的治疗机会。
