Fig. 2

The mechanisms of mitochondrial transfer. a On the one hand, the generation of ROS in stressed mitochondrial recipient cells could activate p53 and its downstream Akt/PI3K/mTOR pathway, leading to the overexpression of TNFαip2, which will promote actin polymerization and TNT formation. On the other hand, the activated p53 in recipient cells could induce the activity of caspase-3 to cleave intracellular S100A4, which will generate a chemical gradient of S100A4 and contribute to the TNT growth direction from initiating cells with a low concentration of S100A4 to targeted cells with a higher concentration of S100A4. b In mitochondrial recipient cells, multiple stress factors will induce the generation of excess ROS, which will then trigger the fragmentation of mitochondria for mitophagy. At the same time, extra damaged mitochondria and other DAMPs will be released from the stressed cell and accepted by mitochondrial donor cells for transmitophagy. The degradation of damaged mitochondria by lysosomes in donor cells will lead to the release of heme, which will then trigger the HO-1 pathway and increase the biogenesis of mitochondria in donor cells, followed by the fusion of mitochondria. Functional mitochondria in donor cells are then transferred to stressed cells. Similar to axonal mitochondrial transport, the movement of mitochondria on microtubules within the TNT might also rely on the Miro1/Milton complex and its connection with kinesin