Mitochondrial signalling in non-fibrotic dilated cardiomyopathies: aortic regurgitation- and tachycardia-induced heat failure

主动脉瓣返流(AI-CM)和心动过速(T-CM)所致的心肌病具有左心室(LV)重构的共同特征：它们是长期可逆的、非纤维化的，并伴随着LV扩张、偏心性肥厚和收缩功能衰竭。尽管这两种疾病的发病率和临床影响都很高，但潜在的信号传递过程尚未得到解决，而且在很大程度上被低估了。我目前的工作揭示了T-CM中线粒体功能障碍的一种特殊模式，特征是增大的线粒体向插入盘移动，底物枯竭，线粒体氧化还原平衡向氧化程度更高的状态转变。然而，没有证据表明氧化应激或相关的纤维化。这些发现与之前报道的心力衰竭病因的特征体征形成对比，如缺血、后负荷增加、遗传性和中毒性扩张型心肌病，其特征是NADH和氧化应激增加，以及线粒体蛋白质组的纤维化和高乙酰化。值得注意的是，我最近可以证明，在T-CM中，线粒体对钙诱导的MPTP开放的倾向增加，给出了肿胀的暗示，并通过线粒体钙发出了潜在的相关信号。我假设：(I)线粒体钙浓度激活了三羧酸循环，并优化了线粒体基质体积的氧化磷酸化能力。这一机制部分抵消了T-CM的线粒体功能障碍，并可通过抑制线粒体钠钙交换而得到支持，从而提供了一个新的药理机会。(Ii)T-CM特异性线粒体功能障碍调节LV重构，阻碍兴奋-收缩偶联(ECC)。(3)这些机制是T-CM和AI-CM作为非纤维性扩张型心肌病的共同病理机制。为了证明我的假设，我将两种罕见的动物模型(心动过速诱发的心力衰竭和介入性主动脉瓣切开术)与一种创新的系统医学方法联系起来，将当前的功能代谢和ECC评估方法与细胞功能成像和现代组学技术相结合，后者破译翻译后信号。我将评估线粒体离子交换和ROS发射的特定抑制剂在体外和体内的治疗潜力。

Aortic regurgitation- (AI-CM) and tachycardia (T-CM) induced cardiomyopathies share characteristics of left ventricular (LV) remodelling: they are over a long period reversible and non-fibrotic and entail LV dilatation, eccentric hypertrophy and systolic failure. Despite high prevalence and clinical impact of both diseases, underlying signalling processes have not been resolved and are largely underacknowledged. My current work revealed a specific pattern of mitochondrial dysfunctions in T-CM, characterized by enlarged mitochondria shifted towards the intercalated discs, depletion of substrates, and a shift of the mitochondrial redox balance towards a more oxidised state. However, there is no evidence for oxidative stress or relevant fibrosis. These findings contrast characteristic signs of previously reported heart failure aetiologies, such as ischemic, increased afterload, hereditary, and toxic dilated cardiomyopathy, which rather feature increases in NADH and oxidative stress as well as fibrosis and hyperacetylation of the mitochondrial proteome. Of note, I could recently show, that the mitochondrial propensity for calcium-induced mPTP-opening increases in T-CM, giving a hint towards swelling and a potentially relevant signalling via mitochondrial calcium. I hypothesise: (I) Mitochondrial calcium concentration activates the tricarboxylic acid cycle and optimises mitochondrial matrix volume with regard to oxidative phosphorylation capacity. This mechanism partially counteracts mitochondrial dysfunction in T-CM and can be supported by inhibition of the mitochondrial sodium calcium exchanger, offering a new pharmacologic opportunity. (II) T-CM specific mitochondrial dysfunction regulates LV remodelling and hampers excitation-contraction coupling (ECC). (III) These mechanisms are a common pathomechanism in T-CM and AI-CM as examples of non-fibrotic dilated cardiomyopathy. To pinpoint my hypothesis, I link two rare animal models (tachypacing-induced heart failure, interventional aortic valvotomy) to an innovative systems medicine approach, combining current methods of functional metabolic and ECC-evaluation with cellular functional imaging and modern -omics technologies, the later deciphering post-translational signalling. I am going to evaluate specific inhibitors of mitochondrial ion-exchange and ROS-emission for their therapeutic potential in-vitro and in-vivo.