Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Am J Physiol Cell Physiol. 2023 Oct 1;325(4):C862-C884. doi: 10.1152/ajpcell.00212.2023. Epub 2023 Aug 14.
Mitochondria control cellular functions through their metabolic role. Recent research that has gained considerable attention is their ability to transfer between cells. This has the potential of improving cellular functions in pathological or energy-deficit conditions, but little is known about the role of mitochondrial transfer in sustaining cellular homeostasis. Few studies have investigated the potential of skeletal muscle as a source of healthy mitochondria that can be transferred to other cell types. Thus, we isolated intermyofibrillar mitochondria from murine skeletal muscle and incubated them with host cells. We observed dose- and time-dependent increases in mitochondrial incorporation into myoblasts. This resulted in elongated mitochondrial networks and an enhancement of bioenergetic profile of the host cells. Mitochondrial donation also rejuvenated the functional capacities of the myoblasts when respiration efficiency and lysosomal function were inhibited by complex I inhibitor rotenone and bafilomycin A, respectively. Mitochondrial transfer was accomplished via tunneling nanotubes, extracellular vesicles, gap junctions, and by macropinocytosis internalization. Murine muscle mitochondria were also effectively transferred to human fibroblast cells having mitochondrial DNA mutations, resulting in augmented mitochondrial dynamics and metabolic functions. This improved cell function by diminishing reactive oxygen species (ROS) emission in the diseased cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated in both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost. This mitochondrial trafficking and bioenergetic reprogramming to maintain and revitalize tissue homeostasis could be a useful therapeutic strategy in treating diseases. In our study, we have shown the potential of mouse skeletal muscle intermyofibrillar mitochondria to be transplanted in myoblasts and human fibroblast cells having mitochondrial DNA mutations. This resulted in an augmentation of mitochondrial dynamics and enhancement of bioenergetic profile in the host cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated into both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost.
线粒体通过其代谢作用控制细胞功能。最近的研究引起了相当大的关注，是它们在细胞之间转移的能力。这有可能改善病理或能量缺乏条件下的细胞功能，但对于线粒体转移在维持细胞内稳态中的作用知之甚少。很少有研究调查骨骼肌作为健康线粒体来源的潜力，这些线粒体可以转移到其他细胞类型。因此，我们从鼠骨骼肌中分离出线粒体并与宿主细胞孵育。我们观察到线粒体与成肌细胞融合的剂量和时间依赖性增加。这导致线粒体网络伸长，并增强了宿主细胞的生物能量特征。当呼吸效率和溶酶体功能分别被复合物 I 抑制剂鱼藤酮和巴弗洛霉素 A 抑制时，线粒体供体还恢复了成肌细胞的功能能力。线粒体转移是通过隧道纳米管、细胞外囊泡、间隙连接和巨胞饮内化来完成的。鼠肌肉线粒体也有效地转移到具有线粒体 DNA 突变的人成纤维细胞中，导致线粒体动力学和代谢功能增强。这通过减少病变细胞中活性氧 (ROS) 的排放来改善细胞功能。我们的研究结果表明，供体骨骼肌中的线粒体可以整合到健康和功能受损的宿主细胞中，导致线粒体结构细化和呼吸增强。这种线粒体运输和生物能量重编程以维持和恢复组织内稳态可能是治疗疾病的一种有用的治疗策略。在我们的研究中，我们已经证明了来自鼠骨骼肌的线立体间纤维的线粒体在成肌细胞和具有线粒体 DNA 突变的人成纤维细胞中被移植的潜力。这导致线粒体动力学的增强和宿主细胞生物能量特征的增强。我们的研究结果表明，供体骨骼肌中的线粒体可以整合到健康和功能受损的宿主细胞中，导致线粒体结构细化和呼吸增强。
