Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart.
Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart.
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Fas 激活的丝氨酸/苏氨酸激酶控制缺血/再灌注心脏中心肌线粒体复合物 I 的功能完整性
DOI：
10.3389/fcell.2020.630421
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发表时间：
2020
影响因子：
5.5
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Chen X;Hu G;Wang Y;Li C;Zhang F
心脏能量平衡严格受线粒体复合体介导的呼吸作用控制。在心脏中，线粒体复合物I在缺血/再灌注（I/R）后极易受到功能和结构的破坏，从而导致心肌能量不足和心肌细胞死亡。Fas激活的丝氨酸/苏氨酸激酶（FASTK）是近年来发现的一种重要的线粒体基因表达和呼吸调节因子。然而，FASTK在心脏I/R过程中的作用尚未确定。在这里，我们表明，FASTK表达下调后I/R心脏。活性氧清除剂N-乙酰-L-半胱氨酸逆转I/R诱导的FASTK下调。FASTK基因缺失加重了I/R诱导的心功能不全，扩大了心肌梗死范围，并增加了心肌细胞凋亡。与野生型对照组相比，FASTK缺陷型心脏表现出较低的NADH脱氢酶亚基-6（MTND 6，编码复合物I亚基的线粒体基因）的mRNA表达，并且更容易受到I/R相关复合物I失活的影响。通过腺病毒介导的基因递送补充FASTK表达恢复了线粒体复合物I的活性，并改善了I/R诱导的心肌细胞死亡，而这些有益的作用被鱼藤酮（一种特异性复合物I抑制剂）的共同治疗所阻断。体内实验进一步证实FASTK的心脏过表达改善了I/R相关的MTND 6下调和线粒体复合物I失活，从而保护心脏免受I/R损伤。总的来说，这些数据首次确定FASTK的下调是I/R过程诱导的线粒体复合物I功能完整性丧失和心脏损伤的直接罪魁祸首。靶向FASTK可能是MI/R干预的一个有希望和有效的策略。
Cardiac energy homeostasis is strictly controlled by the mitochondrial complex-mediated respiration. In the heart, mitochondrial complex I is highly susceptible to functional and structural destroy after ischemia/reperfusion (I/R), thereby contributing to myocardial energy insufficiency and cardiomyocyte death. Fas-activated serine/threonine kinase (FASTK) is recently recognized as a key modulator of mitochondrial gene expression and respiration. However, the role of FASTK in cardiac I/R process is undetermined. Here, we show that FASTK expression was down-regulated in the post-I/R heart. The reactive oxygen species scavenger N-acetyl-L-cysteine reversed I/R-induced FASTK down-regulation. Genetic deletion of FASTK exacerbated I/R-induced cardiac dysfunction, enlarged myocardial infarct size, and increased cardiomyocyte apoptosis. Compared with the wild type control, the FASTK deficient heart exhibited a lower mRNA expression of NADH dehydrogenase subunit-6 (MTND6, a mitochondrial gene encoding a subunit of complex I) and was more vulnerable to I/R-associated complex I inactivation. Replenishment of FASTK expression via adenovirus-mediated gene delivery restored mitochondrial complex I activity and ameliorated cardiomyocyte death induced by I/R, whereas these beneficial effects were blocked by the co-treatment with rotenone, a specific complex I inhibitor. in vivo experiments further confirmed that cardiac overexpression of FASTK ameliorated I/R-related MTND6 down-regulation and mitochondrial complex I inactivation, thereby protecting the heart against I/R injury. Collectively, these data for the first time identify that the down-regulation of FASTK is a direct culprit behind the loss of mitochondrial complex I functional integrity and cardiac injury induced by I/R process. Targeting FASTK might be a promising and effective strategy for MI/R intervention.
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DOI：
10.1073/pnas.0704964104
发表时间：
2007-07-03
影响因子：
11.1
作者：
Simarro, Maria;Mauger, David;Anderson, Paul
通讯作者：
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影响因子：
44.1
作者：
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影响因子：
5.3
作者：
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通讯作者：
Anderson, P
影响因子：
5.5
作者：
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DOI：
10.1038/s41569-018-0074-0
发表时间：
2019-01
期刊：
Nature reviews. Cardiology
影响因子：
--
作者：
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通讯作者：
Galluzzi L