Therapeutic administration of mitochondria has been increasingly explored. However, how these administered mitochondria impact immune response remains to be fully addressed. In this proof-of-concept study, we show that extracellularly added mitochondria to cultured peritoneal macrophages increase phagocytosis and recycling exocytosis that amplifies neuroplasticity mediated by recycled mitochondria transfer. Macrophage activation markers such as Nos2, Arg1, and Cd163 were unchanged at 3 h post-treatment with mitochondria, but whole mitochondria or delivery of mRNAs extracted from whole mitochondria appeared to increase SQSTM1 protein and activate Nrf2-mediated phagocytosis in macrophages, whereas mitochondria treatment did not change the ability of phagocytosis in cultured microglia or astrocytes. Notably, the once engulfed mitochondria in macrophages appear to be released via Rab27a-mediated recycling pathway that were favorably incorporated in mechanically damaged neurons compared with healthy neurons, resulting in accelerating neurite extension in damaged neurons in a direct co-culture model. Altogether, these findings uncover unappreciated mechanisms that mitochondria-treated macrophages upregulate phagocytosis and recycling exocytosis, implicating that engineering mitochondria delivery to macrophages is a new therapeutic intervention to promote neurorecovery in CNS disorders.
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