1 School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, Belfast, UK.
2 Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
J Cereb Blood Flow Metab. 2019 Sep;39(9):1790-1802. doi: 10.1177/0271678X18770331. Epub 2018 Apr 9.
Mortality from perinatal hypoxic-ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on HO release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy.
2010 年，全球围产期缺氧缺血性（HI）脑损伤导致的死亡率达到 115 万，也是婴儿神经功能障碍的主要因素。HI 直接影响线粒体中的氧化磷酸化酶复合物，但 HI 再氧化反应在大脑中的确切机制在很大程度上仍未解决。在诱导出生后 10 天的大鼠 HI 再氧化后，分析了线粒体呼吸链酶的活性，并进行了复合物谱分析。同时测量了线粒体氧消耗时，线粒体复合物 I 构象状态（活性/失活（A/D）转换）对 HO 释放的影响。与细胞色素氧化酶和琥珀酸脱氢酶不同，HI 再氧化在再氧化 4 小时后导致线粒体复合物 I 抑制。在 HI 之后，我们立即观察到复合物 I 的失活（D）形式的含量大量增加。D 形式在通过反向电子转移产生活性氧物种（ROS）方面的活性较低，表明复合物 I 的失活在缺血/再灌注中起着关键作用。我们描述了未成熟大脑对缺血的线粒体反应的一种新机制。HI 诱导复合物 I 失活，以减少再氧化后 ROS 的产生。复合物 I 的延迟激活代表了病理性激活治疗的一个新的线粒体靶标。
