Background and Aims Almost 30% of survivors of myocardial infarction (MI) develop heart failure (HF), in part due to damage caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage post-ischaemic injury and remodelling of the subsequent deteriorated myocardium. Methods This study has shown that a single i.p. dose (2 h post-MI) of the selective small molecule Parkin activator PR-364 reduced mortality, preserved cardiac ejection fraction, and mitigated the progression of HF. To reveal the mechanism of PR-364, a multi-omic strategy was deployed in combination with classical functional assays using in vivo MI and in vitro cardiomyocyte models. Results In vitro cell data indicated that Parkin activation by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced adenosine triphosphate production via improved citric acid cycle, altered accumulation of calcium localization to the mitochondria, and initiated translational reprogramming with increased expression of mitochondrial translational proteins. In mice, PR-364 administered post-MI resulted in widespread proteome changes, indicating an up-regulation of mitochondrial metabolism and mitochondrial translation in the surviving myocardium. Conclusions This study demonstrates the therapeutic potential of targeting Parkin-mediated mitophagy using PR-364 to protect surviving cardiac tissue post-MI from progression to HF.

中文翻译：

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增强的 Parkin 介导的线粒体自噬减轻心肌梗死后不良的左心室重塑：PR-364 的作用


背景和目标 近 30% 的心肌梗死 （MI） 幸存者发展为心力衰竭 （HF），部分原因是功能失调的线粒体积累造成的损害。已知通过 Parkin 介导的线粒体自噬 （线粒体自噬） 进行细胞器质量控制在介导防止 HF 损伤、缺血后损伤和随后恶化的心肌重塑方面发挥作用。方法 这项研究表明，单次腹腔注射剂量 （MI 后 2 小时） 选择性小分子 Parkin 激活剂 PR-364 可降低死亡率，保留心脏射血分数，并减轻 HF 的进展。为了揭示 PR-364 的机制，使用体内 MI 和体外心肌细胞模型部署了多组学策略与经典功能测定相结合。结果 体外细胞数据表明，PR-364 激活 Parkin 增加了线粒体自噬和线粒体生物发生，通过改善柠檬酸循环增强了三磷酸腺苷的产生，改变了钙定位到线粒体的积累，并启动了翻译重编程，线粒体翻译蛋白的表达增加。在小鼠中，MI 后施用 PR-364 导致广泛的蛋白质组变化，表明存活心肌中线粒体代谢和线粒体翻译上调。结论 本研究证明了使用 PR-364 靶向 Parkin 介导的线粒体自噬以保护 MI 后存活的心脏组织免于进展为 HF 的治疗潜力。