Intercellular Mitochondrial Transfer
Mitochondria are cellular organelles that produce about 90% of the chemical energy (ATP) that is required for the survival of cells. This energy is produced through an enzymatic respiration cycle known as the citric acid cycle, or the Krebs cycle. These powerhouse structures possess their own DNA and transcriptional and translational machinery within the cells.
They are thought to be evolutionary originated from specialized bacteria that became incorporated into the cytoplasm, a theory that was formulated by Dr. Lynn Margulis and known as the Endosymbiotic theory .
However, their role can not be limited to energy production. They are also involved in several physiological and pathological processes, including tissue homeostasis, repair of damaged tissue, tumor progression, and immunoregulation .
How Mitochondrial Transfer Works?
Mitochondrial transfer is the relocation of mitochondria from one cell to another, regardless of the cell type. For this, several transfer means are used, including tunneling nanotubes, microvesicle transfer, and extrusion and internalization.
In the process of tunneling nanotubes, mitochondria are transferred through connective membranous tubular protrusions that extend from the plasma membrane of one cell to another.
For the microvesicle transfer, mitochondria are transported within microvesicles that are formed by blebbing of the cellular plasma membrane of a donor cell to another cell (receiving cell). Extrusion and internalization are means of transfer that do not require carriers and involve mitochondria protruding out of the cell and internalization by another cell .
Physiological Mitochondrial Transfer
Although mitochondria transfer was demonstrated in cell cultures (in vitro), their role in cell reprogramming was revealed in cocultured fully differentiated mouse cardiomyocytes (CMs) with hMADs (human multipotent adipose-derived stem cells) .
The researchers demonstrated that mitochondria transfer from hMADs to CMs resulted in somatic reprogramming into stem-like cells, cardiac progenitor-like cells and that the inhibition of this process leads to a significant decrease in their proportion .
These observations were confirmed by another study that showed that mitochondria transfer also happens between bone marrow-mesenchymal stem cells (BM-MSCs) and two other populations of MSCs derived from healthy lung tissues (LT-MSCs) and bronchoalveolar lavage fluid of lung transplant recipients (BAL-MSCs) in vitro .
However, this spontaneous intercellular transfer of mitochondria could also be bidirectional as reported by a study that demonstrated using co-culture experiments of RTCs (renal tubular cells) and mesenchymal multipotent stromal cells (MMSCs).
MMSCs (stem cell-like cells) expressed characteristics that are close to that of the phenotype of RTCs, suggesting that mitochondria transfer from RTCs to MMSCs may have resulted in their reprogramming towards an RTCs-like differentiated phenotype .
Pathological Mitochondrial Transfer
The role of intercellular mitochondrial transfer has been associated with pathological events in the central nervous system (CNS), the cardiovascular system, the musculoskeletal system, and cancer.
In the CNS, mitochondrial transfer was associated with ischemic and hemorrhagic damage rescue, spinal cord injury recovery, neuronal protection of neurons from chemotherapy-induced neurotoxicity, and neurodegeneration.
For example, mitochondria transfer was observed from multipotent MSCs to neurons or astrocytes, where it led to the restoration of respiration in recipient cells and the alleviation of ischemic damage .
In the cardiovascular system, a study demonstrated that transplanted mitochondria enhance oxygen consumption, ATP production, and chemokine secretion within the ischemic myocardial tissue .
In the musculoskeletal system, mitochondria transfer has been suggested to play role in attenuating chondrogenic stress that can lead to chondrocyte death, cartilage degeneration, and post-traumatic osteoarthritis .
Finally, in cancer, Mitochondrial transfer has been shown to occur between tumor cells and other cells within the tumor microenvironment (TME), which promotes tumorigenesis, invasion, metastasis, and resistance to therapy.
The self-protective transfer of mitochondria has been reported in different types of tumors, including acute myeloid leukemia (AML), melanoma, malignant pleural mesothelioma, acute lymphoblastic leukemia (ALL) multiple myeloma, osteosarcoma, astrocytoma, glioblastoma, pheochromocytoma, and in lung, breast, ovarian, prostate, and bladder cancers .
Mitochondria transfer is a fascinating process that contributes to physiological and pathological events. A better understanding of this process will certainly provide new directions in our perceptions of intercellular communications through organelles and empower future therapeutic strategies for regenerative medicine and diseases.
 Margulis, L. and Sagan, D., 1990. Origins of sex: three billion years of genetic recombination. Yale University Press.
 Liu, D., Gao, Y., Liu, J., Huang, Y., Yin, J., Feng, Y., Shi, L., Meloni, B.P., Zhang, C., Zheng, M. and Gao, J., 2021. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduction and Targeted Therapy, 6(1), pp.1-18.
 Acquistapace, A., Bru, T., Lesault, P.F., Figeac, F., Coudert, A.E., Le Coz, O., Christov, C., Baudin, X., Auber, F., Yiou, R. and Dubois‐Randé, J.L., 2011. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor‐like state through partial cell fusion and mitochondria transfer. Stem cells, 29(5), pp.812-824.
 Sinclair, K.A., Yerkovich, S.T., Hopkins, P.M.A. and Chambers, D.C., 2016. Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem cell research & therapy, 7(1), pp.1-10.
 Plotnikov, E.Y., Khryapenkova, T.G., Galkina, S.I., Sukhikh, G.T. and Zorov, D.B., 2010. Cytoplasm and organelle transfer between mesenchymal multipotent stromal cells and renal tubular cells in co-culture. Experimental cell research, 316(15), pp.2447-2455.
 Babenko, V.A., Silachev, D.N., Zorova, L.D., Pevzner, I.B., Khutornenko, A.A., Plotnikov, E.Y., Sukhikh, G.T. and Zorov, D.B., 2015. Improving the post‐stroke therapeutic potency of mesenchymal multipotent stromal cells by cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Translational Medicine, 4(9), pp.1011-1020.
 Masuzawa, A., Black, K.M., Pacak, C.A., Ericsson, M., Barnett, R.J., Drumm, C., Seth, P., Bloch, D.B., Levitsky, S., Cowan, D.B. and McCully, J.D., 2013. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology, 304(7), pp.H966-H982.