Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, 02115, Massachusetts, USA.
Department of Anæsthesia, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Sci Rep. 2017 Dec 12;7(1):17450. doi: 10.1038/s41598-017-17813-0.
Tissue ischemia adversely affects the function of mitochondria, which results in impairment of oxidative phosphorylation and compromised recovery of the affected organ. The impact of ischemia on mitochondrial function has been extensively studied in the heart because of the morbidity and mortality associated with injury to this organ. As conventional methods to preserve cardiac cell viability and contractile function following ischemia are limited in their efficacy, we developed a unique approach to protect the heart by transplanting respiration-competent mitochondria to the injured region. Our previous animal experiments showed that transplantation of isolated mitochondria to ischemic heart tissue leads to decreases in cell death, increases in energy production, and improvements in contractile function. We also discovered that exogenously-derived mitochondria injected or perfused into ischemic hearts were rapidly internalised by cardiac cells. Here, we used three-dimensional super-resolution microscopy and transmission electron microscopy to determine the intracellular fate of endocytosed exogenous mitochondria in human iPS-derived cardiomyocytes and primary cardiac fibroblasts. We found isolated mitochondria are incorporated into cardiac cells within minutes and then transported to endosomes and lysosomes. The majority of exogenous mitochondria escape from these compartments and fuse with the endogenous mitochondrial network, while some of these organelles are degraded through hydrolysis.
组织缺血会对线粒体的功能产生不利影响，导致氧化磷酸化受损，受影响的器官恢复能力下降。由于与该器官损伤相关的发病率和死亡率，缺血对线粒体功能的影响在心脏中得到了广泛研究。由于传统的保存心脏细胞活力和收缩功能的方法在疗效上存在局限性，我们开发了一种独特的方法来保护心脏，即将呼吸功能正常的线粒体移植到受损区域。我们之前的动物实验表明，将分离的线粒体移植到缺血的心脏组织中，可减少细胞死亡、增加能量产生并改善收缩功能。我们还发现，注射或灌注到缺血心脏中的外源性线粒体被心脏细胞迅速内化。在这里，我们使用三维超分辨率显微镜和透射电子显微镜来确定内吞的外源性线粒体在人诱导多能干细胞衍生的心肌细胞和原代心肌成纤维细胞中的细胞内命运。我们发现分离的线粒体在数分钟内被纳入心脏细胞，然后被转运到内体和溶酶体中。大多数外源性线粒体从这些隔室中逃逸并与内源性线粒体网络融合，而其中一些细胞器通过水解被降解。
