Horizontal transfer of mitochondria

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]

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.

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]