Horizontal transfer of mitochondria

Movement of whole mitochondria between cells

Horizontal transfer of mitochondria is the movement of whole mitochondria and mitochondrial DNA between cells. Mitochondria from donor cells are transported and incorporated into the endogenous mitochondrial network of recipient cells contributing to changes in the bioenergetics profile and in other functional properties of recipient cells.[1] Horizontal cell-to-cell transfer of mitochondria and mitochondrial genome can occur among mammalian cells in vitro and in vivo.[2] Mitochondrial transfer supports the exogenous replacement of damaged mitochondria, thereby rescuing mitochondrial defects.[3][4] Stem cells, immortalized cells or primary cells are usually used as mitochondrial donors in most studies.[2] These cells may transfer mitochondria to surrounding cells in their niche, thus affecting cell differentiation, proliferation, tissue homeostasis, development and ageing.[1]

## Mechanism[edit]

Horizontal transfer of mitochondria is mediated by actin-rich membrane protrusions named tunneling nanotubes (TNTs).[5] The establishment of a nanotube begins with the formation of a filopodium-like membrane protrusion that retracts after reaching the recipient cell, leaving an ultrafine structure that is separated from the substrate.[1] Chemical inhibitors or mechanical stress impairs the formation of TNTs and reduces mitochondrial exchange.[1][6] On the other hand, certain types of stress agents such as doxorubicin[7] or ethidium bromide[8] increase TNT formation. Other proposed mechanisms of transfer include membrane microvesicles, cell fusion or mitochondrial extrusion.[1]

## In vitro transfer[edit]

The first evidence of functional mitochondrial transfer in vitro has been documented between human mesenchymal stem cells (hMSCs) and human lung carcinoma cells. Healthy mitochondria from hMSCs moved to recipient lung carcinoma cells with nonfunctional mitochondria and repaired their function.[9] Intercellular transfer of mitochondria in culture has been documented from MSCs and endothelial cells to breast cancer cell lines, ovarian cancer cell lines or to osteosarcoma cell line.[10] Mitochondrial transfer can occur also between cancer cells such as mesothelioma[11] and laryngeal carcinoma cells.[12] Non-tumor cells such as human renal epithelial cells, human retinal pigment epithelial cells or human monocyte-derived macrophages have been shown to transfer their mitochondria as well.[13] All these data suggest that this phenomenon, regardless of the exact mechanisms involved, may be a fundamental physiological process well worthwhile exploring in a whole organism setting.

## In vivo transfer[edit]

One of the first evidences of in vivo horizontal mitochondrial gene transfer was found in a transmissible canine venereal tumor (CTVT), highly adapted cancer transmitted during mating of feral dogs. Phylogenetic analyses of mitochondrial sequences revealed that CTVT cells periodically acquire mitochondria from its host and ensure overcoming high mutation rate that would promote the accumulation of deleterious mutations in their own mitochondria and long-term survival.[14] Transfer of intact mitochondria can contribute to tissue repair in vivo. Bone marrow-derived stem cells (BMSCs) injected into mice with acute lung injury transfer their mitochondria to lung alveoli cells and protect them against injury.[15] Overexpression of Miro1, a protein connecting mitochondria to cytoskeletal motor proteins, leads to enhanced transfer of mitochondria from MSCs into stressed epithelial cells via TNTs in mice.[16] In vivo horizontal transfer of mitochondria can occur in cancer cells which upon mitochondrial damage acquire mtDNA from surrounding donor healthy cells. This process restores transcription and translation of mtDNA-encoded genes as well as respiration.[17]

## References[edit]

1. ^ a b c d e Torralba, D.; Baixauli, F.; Sánchez-Madrid, F. (2016). "Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer". Frontiers in Cell and Developmental Biology. 4 (107). doi:10.3389/fcell.2016.00107. PMC 5039171. PMID 27734015.
2. ^ a b Berridge, M.V; McConnell, M.J; Grasso, C.; Bajzikova, M.; Kovarova, J.; Neuzil, J. (2016). "Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches". Current Opinion in Genetics & Development. 38: 75–82. doi:10.1016/j.gde.2016.04.003. PMID 27219870.
3. ^ Patananan, A.N; Wu, T.H.; Chiou, P.Y.; Teitell, M. A. (2016). "Modifying the Mitochondrial Genome". Cell Metabolism. 23 (5): 785–796. doi:10.1016/j.cmet.2016.04.004. PMC 4864607.
4. ^ Hayakawa, K.; Esposito, E.; Wang, X.; Terasaki, Y.; Liu, Y.; Xing, Ch.; Ji, X.; Lo, E.H. (2016). "Transfer of mitochondria from astrocytes to neurons after stroke". Nature. 535 (7613): 551–555. Bibcode:2016Natur.535..551H. doi:10.1038/nature18928. PMC 4968589. PMID 27466127.
5. ^ Rustom, A.; Saffrich, R.; Markovic, I.; Walther, P.; Gerdes, H.H (2004). "Nanotubular highways for intercellular organelle transport". Science. 303 (5660): 1007–1010. Bibcode:2004Sci...303.1007R. doi:10.1126/science.1093133. PMID 14963329.
6. ^ Bukoreshtliev, N.V.; Wang, X.; Hodneland, E.; Gurke, S.; Barroso, J.F.V.; Gerdes, H.H (2009). "Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells". FEBS Letters. 583 (9): 1481–1488. doi:10.1016/j.febslet.2009.03.065. PMID 19345217.
7. ^ Yasuda, K.; Park, H.Ch.; Ratliff, B.; Addabbo, F.; Hatzopoulos, A.K.; Chander, P.; Goligorsky, M.S. (2010). "Adriamycin Nephropathy". The American Journal of Pathology. 176 (4): 1685–1695. doi:10.2353/ajpath.2010.091071. PMC 2843460. PMID 20167859.
8. ^ Cho, Y.M.; Kim, J.H.; Kim, M.; Park, S.J.; Koh, S.H.; Ahn, H.S.; Kang, G.H.; Lee, J.B; Park, K.S.; Lee, H.K.; Moran, M. (2012). "Mesenchymal Stem Cells Transfer Mitochondria to the Cells with Virtually No Mitochondrial Function but Not with Pathogenic mtDNA Mutations". PLoS ONE. 7 (3): e32778. Bibcode:2012PLoSO...732778C. doi:10.1371/journal.pone.0032778. PMC 3295770. PMID 22412925.
9. ^ Spees, J.L; Olson, S.D; Whitney, M.J; Prockop, D.J (2006). "Mitochondrial transfer between cells can rescue aerobic respiration". Proc Natl Acad Sci USA. 103 (5): 1283–1288. Bibcode:2006PNAS..103.1283S. doi:10.1073/pnas.0510511103. PMC 1345715. PMID 16432190.
10. ^ Neuzil, J.; Dong, L.; Berridge, M.V. (2015). "Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer". Cancer Research. 75 (16): 3203–3208. doi:10.1158/0008-5472.CAN-15-0859. ISSN 0008-5472.
11. ^ Lou, E.; Fujisawa, S.; Morozov, A.; Barlas, A.; Romin, Y.; Dogan, Y.; Gholami, S.; Moreira, A.L.; Manova-Todorova, K.; Moore, M. A. S.; Yang, P.CH (2012). "Tunneling Nanotubes Provide a Unique Conduit for Intercellular Transfer of Cellular Contents in Human Malignant Pleural Mesothelioma". PLoS ONE. 7 (3): e33093. Bibcode:2012PLoSO...733093L. doi:10.1371/journal.pone.0033093. PMC 3302868. PMID 22427958.
12. ^ Antanavičiūtė, I.; Rysevaitė, K.; Liutkevičius, V.; Marandykina, A.; Rimkutė, L.; Sveikatienė, R.; Uloza, V.; Skeberdis, V.; Scemes, E. (2014). "Long-Distance Communication between Laryngeal Carcinoma Cells". PLoS ONE. 9 (6): e99196. Bibcode:2014PLoSO...999196A. doi:10.1371/journal.pone.0099196. PMC 4063716. PMID 24945745.
13. ^ Caicedo, A.; Aponte, P.M.; Cabrera, F.; Hidalgo, C.; Khoury, M. (2017). "Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications". Stem Cells International. 2017: 1–23. doi:10.1155/2017/7610414. PMC 5511681.
14. ^ Rebbeck, C.A; Leroi, A.M; Burt, A. (2011). "Mitochondrial capture by a transmissible cancer". Science. 331 (6015): 303. Bibcode:2011Sci...331..303R. doi:10.1126/science.1197696. PMID 21252340.
15. ^ Islam, M.N; Das, S.R; Emin, M.T; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D.J; Quadri, S.K; Bhattacharya, S.; Bhattacharya, J. (2012). "Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury". Nature Medicine. 18 (5): 759–765. doi:10.1038/nm.2736. PMC 3727429. PMID 22504485.
16. ^ Ahmad, T.; Mukherjee, S.; Pattnaik, B.; Kumar, M.; Singh, S.; Kumar, M.; et al. (2014). "Miro1 regulates intercellular mitochondrial transport and enhances mesenchymal stem cell rescue efficacy". EMBO J. 33 (9): 994–1010. doi:10.1002/embj.201386030. PMC 4193933. PMID 24431222.
17. ^ Tan, A.S; Baty, J.W; Dong, L.F; Bezawork-Geleta, A.; Endaya, B.; Goodwin, J.; Bajzikova, M.; Kovarova, J.; Peterka, M.; Yan, B.; Pesdar, E.A; Sobol, M.; Filimonenko, A.; Stuart, S.; Vondrusova, M.; Kluckova, K.; Sachaphibulkij, K.; Rohlena, J.; Hozak, P.; Truksa, J.; Eccles, D.; Haupt, L.M; Griffiths, L.R; Neuzil, J.; Berridge, M.V (2015). "Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA". Cell Metabolism. 21 (1): 81–91. doi:10.1016/j.cmet.2014.12.003. PMID 25565207.