Fig. 1. Mitochondrial secretion, transplantation, and biological effects on target cells.

Donor cells extracellularly secrete microvesicles containing mitochondria through outward budding, exosomes containing mitochondrial-derived vesicles (MDVs) through the fusion of multivesicular bodies (MVBs) with the plasma membrane, free/naked mitochondria through an unclarified mechanism, or depolarized mitochondria through the secretory autophagy pathway. Mitochondrial fission and CD38/cADPR signaling have been suggested to mediate extracellular mitochondrial secretion. Mitochondrial transplantation involves the isolation of mitochondria from autologous tissues such as skeletal muscle or healthy cells such as mesenchymal stem cells (MSCs) via differential centrifugation or filtration methods and subsequent local or systemic administration. Although the administration of freeze-stored mitochondria has been described, the injection of freshly isolated mitochondria appears to be ideal. Mitochondria that are secreted extracellularly or introduced exogenously can be taken up by recipient cells through membrane fusion or endocytosis. Extracellular mitochondria may also interact with recipient cell surface receptors such as heparan sulfate proteoglycans (HSPGs) for uptake. Once inside the cells, the mitochondria integrate with the host mitochondrial network or activate signaling pathways mediated by their cargo. Although further investigation is needed, secreted or transplanted mitochondria have also been suggested to exert extracellular effects. Overall, these reactions elicit major biological effects on recipient cells, including increases in mitochondrial respiration and cell survival and the regulation of the oxidative stress response, the inflammatory response, and cell differentiation or maturation.