Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.

Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.