Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission-associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development.

中文翻译：

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低氧诱导的丝素蛋白与Drp1的相互作用导致线粒体高裂变相关的心肌衰老。

通过线粒体和肌动蛋白细胞骨架之间异常相互作用的线粒体动力学缺陷已被越来越多地认为是心肌梗死（MI）后心脏脆性的关键决定因素。动力蛋白相关蛋白1（Drp1），一种线粒体裂变加速因子，通过与肌动蛋白的相互作用在裂变部位被局部激活。在这里，我们报告肌动蛋白结合蛋白丝蛋白A充当MI后小鼠Drp1和介导的线粒体裂变相关心肌衰老的鸟嘌呤核苷酸交换因子。在以线粒体高裂变为特征并伴有心肌衰老的梗塞周围区域，纤维蛋白A与Drp1共同定位于线粒体周围。低氧应激以大鼠肌动蛋白结合依赖性的方式诱导纤维蛋白A与Drp1的GTPase结构域相互作用，并以肌动蛋白结合依赖性的方式增加Drp1的活性。A1545T filamin突变体的表达，增强肌动蛋白的聚集，促进了在常氧下的线粒体超裂变。此外，西尼地平对Drp1-filamin A相互作用的药理学扰动抑制了MI后线粒体高裂变相关的心肌衰老和心力衰竭。总之，这些数据表明，Drp1与纤维蛋白和肌动蛋白细胞骨架的结合可导致MI后心脏的脆弱性，并提示西尼地平的潜在用途，以及为创新性Drp1抑制剂的开发提供起点。增强肌动蛋白的聚集，促进常氧下的线粒体高裂变。此外，西尼地平对Drp1-filamin A相互作用的药理学扰动抑制了MI后线粒体高裂变相关的心肌衰老和心力衰竭。总之，这些数据表明，Drp1与纤维蛋白和肌动蛋白细胞骨架的结合可导致MI后心脏的脆弱性，并提示西尼地平的潜在用途，以及为创新性Drp1抑制剂的开发提供起点。增强肌动蛋白的聚集，促进常氧下的线粒体高裂变。此外，西尼地平对Drp1-filamin A相互作用的药理学扰动抑制了MI后线粒体高裂变相关的心肌衰老和心力衰竭。总之，这些数据表明，Drp1与纤维蛋白和肌动蛋白细胞骨架的结合可导致MI后心脏的脆弱性，并提示西尼地平的潜在用途，以及为创新性Drp1抑制剂的开发提供起点。