Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer
Yi Wang, Hao‐Yuan Yu, Zi-Juan Yi, Lian‐Yu Qi, Jingsong Yang, Hai-Xin Xie, Min Zhao, Na-Hui Liu, Jiaqi Chen, Tian‐Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu‐Lin Jiang
Abstract
Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber’s hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders. In mitochondria transplantation, the limited activity and yield of mitochondria constrain their clinical application for mitochondrial diseases. Here, authors develop a method for producing mitochondria-enriched extracellular vesicles, which offer high-quality, abundant mitochondrial material for transplantation.