Mitochondrial transplantation for therapeutic use.
Mitochondrial transplantation for therapeutic use.
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DOI：
10.1186/s40169-016-0095-4
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发表时间：
2016-03
影响因子：
10.6
通讯作者：
Cowan DB
中科院分区：
文献类型：
--
作者：
McCully JD;Levitsky S;Del Nido PJ;Cowan DB
线粒体在体内绝大多数细胞的稳态中起着关键作用。在线粒体占心肌细胞总体积30%的心肌中，血流的暂时性衰减或阻塞以及因此向心肌细胞的氧递送（缺血）严重改变线粒体结构和功能。这些线粒体结构和功能的改变发生在缺血期间，并在血流和氧输送到心肌恢复后继续，并显著降低心肌收缩功能和心肌细胞存活。我们假设，缺血损伤的线粒体的增加或替换将提供一种机制，以增强细胞功能和细胞救援后恢复血流。为了验证这一假设，我们使用了心肌缺血和再灌注模型。我们的研究表明，移植自体线粒体，从病人自己的身体分离，然后在早期再灌注期间直接注射到心肌中，增强了缺血期间受损的天然线粒体的功能，并增强了心肌缺血后的功能恢复和细胞活力。移植的线粒体在细胞外和细胞内都起作用。在细胞外，移植的线粒体增强高能合成和细胞腺苷三磷酸储存并改变心肌蛋白质组。一旦内化，移植的线粒体拯救细胞功能并替换受损的线粒体DNA。不存在免疫或自身免疫反应，并且不存在作为移植线粒体的结果的促心律失常。我们的研究和其他人的研究表明，线粒体移植在许多细胞类型和疾病中是有效的。这些包括心脏和骨骼肌、肺和肝组织和细胞以及神经元组织。在这篇综述中，我们讨论了导致线粒体功能障碍的机制和对细胞功能的影响。我们提供了一种分离线粒体的方法，以使临床相关性，我们讨论了我们和其他人用于线粒体的摄取和内化的方法。我们预见，线粒体移植将是所有临床医生和外科医生用于治疗各种缺血性疾病、线粒体疾病和相关疾病的一种有价值的治疗方法。
Mitochondria play a key role in the homeostasis of the vast majority of the body’s cells. In the myocardium where mitochondria constitute 30 % of the total myocardial cell volume, temporary attenuation or obstruction of blood flow and as a result oxygen delivery to myocardial cells (ischemia) severely alters mitochondrial structure and function. These alterations in mitochondrial structure and function occur during ischemia and continue after blood flow and oxygen delivery to the myocardium is restored, and significantly decrease myocardial contractile function and myocardial cell survival. We hypothesized that the augmentation or replacement of mitochondria damaged by ischemia would provide a mechanism to enhance cellular function and cellular rescue following the restoration of blood flow. To test this hypothesis we have used a model of myocardial ischemia and reperfusion. Our studies demonstrate that the transplantation of autologous mitochondria, isolated from the patient’s own body, and then directly injected into the myocardial during early reperfusion augment the function of native mitochondria damaged during ischemia and enhances myocardial post-ischemic functional recovery and cellular viability. The transplanted mitochondria act both extracellularly and intracellularly. Extracellularly, the transplanted mitochondria enhance high energy synthesis and cellular adenosine triphosphate stores and alter the myocardial proteome. Once internalized the transplanted mitochondria rescue cellular function and replace damaged mitochondrial DNA. There is no immune or auto-immune reaction and there is no pro-arrhythmia as a result of the transplanted mitochondria. Our studies and those of others demonstrate that mitochondrial transplantation can be effective in a number of cell types and diseases. These include cardiac and skeletal muscle, pulmonary and hepatic tissue and cells and in neuronal tissue. In this review we discuss the mechanisms leading to mitochondrial dysfunction and the effects on cellular function. We provide a methodology for the isolation of mitochondria to allow for clinical relevance and we discuss the methods we and others have used for the uptake and internalization of mitochondria. We foresee that mitochondrial transplantation will be a valued treatment in the armamentarium of all clinicians and surgeons for the treatment of varied ischemic disorders, mitochondrial diseases and related disorders.