Sabbah Hani N, Alder Nathan N, Sparagna Genevieve C, Bruce James E, Stauffer Brian L, Chao Luke H, Pitceathly Robert D S, Maack Christoph, Marcinek David J
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Henry Ford Health, Detroit, MI, USA.
Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA.
Biomed Pharmacother. 2025 Jun;187:118056. doi: 10.1016/j.biopha.2025.118056. Epub 2025 Apr 27.
Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide's MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide's ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide's MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.
线粒体是细胞中对新陈代谢、信号传导和细胞存活至关重要的核心结构。线粒体功能障碍在衰老过程以及一系列广泛的疾病状态中起着核心作用。艾拉米肽是一种新型的靶向线粒体的肽，目前正在研究用于治疗几种与线粒体功能障碍相关的疾病。本综述总结了最近的数据，这些数据扩展了我们对艾拉米肽作用机制的理解。艾拉米肽是一种潜在的一流疗法，靶向线粒体内膜。尽管最初对艾拉米肽作用机制的描述涉及清除活性氧，但在过去十年中，对这种肽如何影响线粒体生物能量学有了重大扩展。不同的研究团队证实了艾拉米肽与心磷脂的结合特性，并发现了艾拉米肽 - 心磷脂相互作用的新结果。特别是，新研究表明艾拉米肽可调节线粒体膜的静电电位，并组装在线粒体生理学中起核心作用的依赖心磷脂的蛋白质。这些作用有助于艾拉米肽改善线粒体功能、结构和生物能量学的能力。在动物研究中，在心脏和骨骼肌肌病以及眼部疾病模型中观察到了艾拉米肽介导的器官功能障碍改善。最近已经完成了多项关于艾拉米肽的临床试验，本文还提供了针对巴特综合征、原发性线粒体肌病和年龄相关性黄斑变性的结果总结。艾拉米肽作为线粒体疾病的潜在治疗方法继续显示出前景。新的基础科学进展提高了对艾拉米肽作用机制的理解，从而能够更好地理解艾拉米肽 - 心磷脂相互作用的分子后果。
