Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy.
Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy.
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DOI：
10.1111/jnc.13590
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发表时间：
2016-06
影响因子：
4.7
通讯作者：
Fiskum G
中科院分区：
文献类型：
--
作者：
Demarest TG;Schuh RA;Waddell J;McKenna MC;Fiskum G
在新生儿缺氧缺血性脑病的临床和实验研究中，男性对长期认知缺陷的易感性增加得到了很好的描述。虽然已知细胞死亡信号通路是两性二态的，但在大多数继发性细胞死亡之前，性别依赖的病理生理机制尚未被描述。线粒体功能障碍有助于脑缺氧缺血（HI）后细胞死亡。有几条线索表明，成年哺乳动物的线粒体代谢存在性别差异。因此，本研究验证了HI后男性脑线粒体呼吸损伤和相关氧化应激比女性更严重的假设。男性HI后，氧化磷酸化过程中最大脑线粒体呼吸受损程度是男性的两倍。假雌性小鼠大脑中的内源性抗氧化剂谷胱甘肽含量比雄性小鼠高30%。雌性在HI损伤后也表现出谷胱甘肽过氧化物酶（GPx）活性的增加。相反，雄性显示线粒体GPx4蛋白水平和线粒体GPx活性降低。此外，损伤雄性小鼠的皮质、鼻周皮质和海马中氧化蛋白羰基化水平增加了3 - 4倍，而雌性小鼠则没有。这些数据为性别依赖的线粒体呼吸功能障碍和氧化损伤提供了第一个证据，这可能导致男性对HI后不良长期结局的相对易感性。
Increased male susceptibility to long-term cognitive deficits is well described in clinical and experimental studies of neonatal hypoxic-ischemic encephalopathy. While cell death signaling pathways are known to be sexually dimorphic, a sex-dependent pathophysiological mechanism preceding the majority of secondary cell death has yet to be described. Mitochondrial dysfunction contributes to cell death following cerebral hypoxic-ischemia (HI). Several lines of evidence suggest there are sex differences in the mitochondrial metabolism of adult mammals. Therefore, this study tested the hypothesis that brain mitochondrial respiratory impairment and associated oxidative stress is more severe in males than females following HI. Maximal brain mitochondrial respiration during oxidative phosphorylation was two-fold more impaired in males following HI. The endogenous antioxidant glutathione was 30% higher in the brain of sham females compared to males. Females also exhibited increased glutathione peroxidase (GPx) activity following HI injury. Conversely, males displayed a reduction in mitochondrial GPx4 protein levels and mitochondrial GPx activity. Moreover, a 3 to 4-fold increase in oxidative protein carbonylation was observed in the cortex, perirhinal cortex, and hippocampus of injured males, but not females. These data provide the first evidence for sex dependent mitochondrial respiratory dysfunction and oxidative damage which may contribute to the relative male susceptibility to adverse long-term outcomes following HI.