Ed p53 in recipient cells could induce the activity of caspase-3 to cleave intracellular S100A4, that will produce a chemical gradient of S100A4 and contribute for the TNT growth direction from initiating cells with a low concentration of S100A4 to targeted cells with a greater concentration of S100A4. b In mitochondrial recipient cells, various tension factors will induce the generation of excess ROS, which will then trigger the fragmentation of mitochondria for mitophagy. In the very same time, extra damaged mitochondria and also other DAMPs will probably be released from the stressed cell and accepted by mitochondrial donor cells for transmitophagy. The degradation of broken mitochondria by lysosomes in donor cells will result in the release of heme, that 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 may also depend on the Miro1/Milton complicated and its connection with kinesinand MVs was inhibited in Cx43-mutated BMSCs, which potentially resulted in the failure of attachment among BMSCs and alveoli. Consequently, the subsequent mitochondrial transfer and lung injury rescue have been also attenuated. Nonetheless, some other studies also reported the involvement of Cx43 in TNT formation.85,126,127 Osswald et al.85 verified that mitochondria traveledquickly within the tumor membrane microtubule network, and that Cx43 was frequently positioned at the intersection location of two diverse microtubules, which facilitated calcium propagation across tumor microtubules. The knockdown of Cx43 reduced synchronicity of intercellular calcium waves plus the proportion of astrocytoma cells with various microtubules, which indicated theSignal Transduction and Targeted Therapy (2021)6:Intercellular mitochondrial transfer as a suggests of tissue revitalization Liu et al.role of Cx43 in stabilization of intercellular membrane microtubules in tumor cells. Additionally, Cx43 was also reported to be abundant inside the osteocyte dendritic network to promote the osteocyte coupling and survival,128 indicating that Cx43 may possibly also contribute towards the transfer of mitochondria between osteocytes by strengthening intercellular contacts. Even though the mechanisms underlying the function of gap junction proteins in intercellular mitochondrial transfer require further investigation, it is attainable that Cx43 contributes for the connection among TNTs plus the anchored membranous structure. As reported, the intercellular movement of mitochondria through TNTs requires the transport carrier referred to as Miro1, which is a calcium-sensitive Rho-GTPase within the outer mitochondrial membrane.31,32,60,69 In neurons, Miro1 acts as a mitochondria-loaded vehicle that interacts with mitofusion1/2 and combines using the kinesin-1 molecular motor via the Milton adaptor protein (TRAK1/2 and OIP106/98) to type a complicated, as a result enabling the shuttling of mitochondria along microtubules.129,130 Ahmad et al.69 revealed the effect of Miro1 on promoting Testicular Receptor 4 Proteins Synonyms TNT-mediated intercellular mitochondrial transfer from MSCs to stressed epithelial cells. The overexpression of Miro1 in MSCs enhanced the transfer of mitochondria as well as the rescue of injured epithelial cells, even though Miro1 knockdown in MSCs led to the Mitogen-Activated Protein Kinase 13 (p38 delta/MAPK13) Proteins Purity & Documentation inhibition of mitochondrial transfer in addition to a reduction in rescue efficienc.