1Division of Neonatology, Department of Pediatrics, Columbia University, New York, New York.
2Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York.
Antioxid Redox Signal. 2019 Sep 20;31(9):608-622. doi: 10.1089/ars.2018.7693. Epub 2019 Jul 1.
Brain ischemia/reperfusion (I/R) is associated with impairment of mitochondrial function. However, the mechanisms of mitochondrial failure are not fully understood. This work was undertaken to determine the mechanisms and time course of mitochondrial energy dysfunction after reperfusion following neonatal brain hypoxia-ischemia (HI) in mice. HI/reperfusion decreased the activity of mitochondrial complex I, which was recovered after 30 min of reperfusion and then declined again after 1 h. Decreased complex I activity occurred in parallel with a loss in the content of noncovalently bound membrane flavin mononucleotide (FMN). FMN dissociation from the enzyme is caused by succinate-supported reverse electron transfer. Administration of FMN precursor riboflavin before HI/reperfusion was associated with decreased infarct volume, attenuation of neurological deficit, and preserved complex I activity compared with vehicle-treated mice. , the rate of FMN release during oxidation of succinate was not affected by the oxygen level and amount of endogenously produced reactive oxygen species. Our data suggest that dissociation of FMN from mitochondrial complex I may represent a novel mechanism of enzyme inhibition defining respiratory chain failure in I/R. Strategies preventing FMN release during HI and reperfusion may limit the extent of energy failure and cerebral HI injury. The proposed mechanism of acute I/R-induced complex I impairment is distinct from the generally accepted mechanism of oxidative stress-mediated I/R injury. Our study is the first to highlight a critical role of mitochondrial complex I-FMN dissociation in the development of HI-reperfusion injury of the neonatal brain. 31, 608-622.
脑缺血/再灌注（I/R）与线粒体功能障碍有关。然而，线粒体衰竭的机制尚不完全清楚。本研究旨在确定新生鼠脑缺氧缺血（HI）后再灌注时线粒体能量功能障碍的机制和时程。HI/再灌注降低了线粒体复合物 I 的活性，这种活性在再灌注 30 分钟后恢复，然后在 1 小时后再次下降。复合物 I 活性的降低与非共价结合的膜黄素单核苷酸（FMN）含量的丧失平行发生。FMN 从酶上的解离是由琥珀酸支持的反向电子转移引起的。HI/再灌注前给予 FMN 前体核黄素与对照组相比，可减少梗死体积、减轻神经功能缺损，并保持复合物 I 活性。此外，在氧水平和内源性产生的活性氧的数量不影响琥珀酸氧化过程中 FMN 的释放率。我们的数据表明，FMN 从线粒体复合物 I 上的解离可能代表一种新的酶抑制机制，定义了 I/R 中的呼吸链衰竭。在 HI 和再灌注期间防止 FMN 释放的策略可能会限制能量衰竭和脑 HI 损伤的程度。所提出的急性 I/R 诱导的复合物 I 损伤的机制与普遍接受的氧化应激介导的 I/R 损伤机制不同。本研究首次强调了线粒体复合物 I-FMN 解离在新生鼠脑 HI 再灌注损伤中的关键作用。Free Radic Biol Med. 2012 Nov 15;53(10):1934-43.
