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

线粒体电子传输链(ETC)由蛋白质复合体组成，它将电子从NADH/FADH2传递到氧中，从而将质子从基质中抽出来。这些质子通过络合物V的回流导致ATP的生成。电子流障碍与线粒体功能障碍有关，线粒体功能障碍与收缩功能障碍有关。当电子传递被阻断时，只存在于低等生物中的一种替代氧化酶(AOX)被激活。它通过直接将电子转移到氧来绕过络合物III和IV。因此，活性氧(ROS)和三磷酸腺苷(ATP)的产生被减少。在转移到动物模型和人类细胞培养中后，AOX的保护作用在各种病理中被证明。AOX可改善脂多糖诱导的炎症小鼠的存活率，减轻果蝇帕金森病模型的运动缺陷，并诱导对ETC毒素抗霉素A的抵抗。这些结果提示AOX在其他临床相关的病理中具有保护作用。我们在心脏压力超负荷的大鼠模型中证明了ETC和收缩功能障碍之间的联系。蛋白质组改变，ETC复合体活性降低，ROS的出现明显增加。我们现在的目标是研究AOX在心脏压力超负荷中的作用。在新近产生的AOX转基因大鼠和野生型大鼠中，横动脉缩窄将导致心脏压力超负荷。在存活的同时，超声心动图将在压力超负荷6周和10周后测量心脏功能，并分离心肌线粒体。他们的呼吸能力、复合活动和ROS产生将被测量。我们预计AOX可以预防心功能障碍，并在慢性压力超负荷期间改善存活率，这可能与ROS产生减少有关。这些对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具有产生新的心力衰竭治疗选择的潜力。

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.