Alternative Oxidase as Rescue-Mechanism for Mitochondrial Dysfunction in Heart Failure

替代氧化酶作为心力衰竭线粒体功能障碍的救援机制

• 批准号: 421969070
• 负责人: Dr. Christina Schenkl
• 金额: --
• 依托单位: Klinik für Herz- und Thoraxchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/421969070?language=en
• 关键词: Alternative; Oxidase; Rescue; Mechanism; Mitochondrial

The mitochondrial electron transport chain (ETC) consists of protein complexes that transfer electrons from NADH/FADH2 to oxygen thereby pumping protons out of the matrix. The backflow of these protons through complex V results in the generation of ATP. A disturbance of electron flow is linked to mitochondrial dysfunction that is related to contractile dysfunction. An alternative oxidase (AOX) that functionally exists only in lower organisms is activated when electron transport is blocked. It bypasses complexes III and IV by transferring electrons to oxygen directly. Thus, the production of reactive oxygen species (ROS) and ATP is reduced. After the transfer into animal models and human cell cultures, a protective effect of AOX was demonstrated in various pathologies. AOX improved the survival of LPS-induced inflammation in mice, alleviated locomotive defects in a model for Parkinson’s disease in Drosophila melanogaster and induced resistance against the ETC toxin antimycine. These results suggest protective effects of AOX in other clinically relevant pathologies. We demonstrated a link between ETC- and contractile dysfunction in a rat model of cardiac pressure overload. The proteome was altered, the activity of the ETC complexes was reduced and the emergence of ROS was heavily increased. We now aim to examine the effects of AOX in cardiac pressure overload. In recently generated AOX-transgenic and in wild type rats, cardiac pressure overload will be induced by transverse aortic constriction. In parallel to survival, cardiac function will be measured by echocardiography after 6 and 10 weeks of pressure overload and cardiac mitochondria will be isolated. Their respiratory capacity, complex activity and ROS-production will be measured. We expect that AOX prevents cardiac dysfunction and improves survival during chronic pressure overload presumably associated with reduced ROS production. These mechanistic analyses of mitochondrial function will set the stage for our further research activities. AOX bears the potential for the generation of new therapeutic options in heart failure.

线粒体电子传递链（ETC）由蛋白质复合物组成，它将电子从NADH/FADH2转移到氧中，从而将质子从基质中抽出。这些质子通过复合体V回流产生ATP。电子流紊乱与线粒体功能障碍有关，而线粒体功能障碍与收缩功能障碍有关。另一种氧化酶（AOX）在功能上只存在于低等生物中，当电子传递受阻时，它就会被激活。它通过直接将电子转移到氧而绕过配合物III和IV。因此，活性氧（ROS）和ATP的产生减少。在转移到动物模型和人类细胞培养后，AOX在各种病理中显示出保护作用。AOX提高了lps诱导的小鼠炎症的存活率，减轻了黑腹果蝇帕金森病模型中的运动缺陷，并诱导了对ETC毒素抗疫苗的抗性。这些结果提示AOX在其他临床相关病理中具有保护作用。我们在心脏压力过载的大鼠模型中证明了ETC和收缩功能障碍之间的联系。蛋白质组发生改变，ETC复合物活性降低，ROS出现大量增加。我们现在的目的是研究AOX在心脏压力过载中的作用。在新产生的aox转基因大鼠和野生型大鼠中，主动脉横缩会引起心脏压力过载。在生存的同时，在压力过载6周和10周后用超声心动图测量心功能，并分离心脏线粒体。他们的呼吸能力，复杂活动和ros生成将被测量。我们预计，AOX可以预防心功能障碍，并提高慢性压力过载期间的生存率，这可能与ROS产生减少有关。这些线粒体功能的机制分析将为我们进一步的研究活动奠定基础。AOX有潜力为心力衰竭提供新的治疗选择。