Mitochondria on the Move
When something in our body stops working properly, it is oftentimes possible to remedy the situation by transplanting the organ or a part of it. Moreover, many pathologies can be resolved by transplanting haematopoietic stem cells or gut microbiome. Even blood transfusion can be considered transplantation. Almost 20 years ago, mammalian cells were shown to be also capable of a “transplantation” or “transfusion” of sorts: intercellular transfer of organelles. Such organelles, including mitochondria, may be exchanged by cells, or even usurped by them.
Mitochondria are organelles most famous for their key role in producing vast amounts of ATP (adenosine triphosphate, “the energy currency of the cell”) by means of oxidative phosphorylation. However, mitochondria are also responsible for synthesising a variety of compounds, including pyrimidines and other components of nucleotides, the building blocks of nucleic acids. Moreover, mitochondria contribute to the regulation of various processes such as cell death, proliferation, differentiation, et cetera.
A cell containing too many damaged mitochondria finds itself in a tight spot. For example, delayed tumour growth resulted from a lack of functional mitochondria in tumour cells. The reason behind the delayed growth does not seem to be linked to the cells being unable to meet their energy demands. Cancer cells primarily acquire ATP through glycolysis, which does not rely on functional mitochondria. Their proliferation and tumorigenic capacity seem to be hindered by the non-functional pyrimidine synthesis pathway. Cancer cells with non-functional mitochondria were able to overcome the lack of pyrimidine synthesis pathway and produce a tumour after a few weeks. It was only then when they managed to “steal” healthy mitochondria from surrounding stromal cells. The stolen mitochondria were acquired through thin cytoplasmic bridges termed tunnelling nanotubes (TNTs).
The transfer of mitochondria between cells—horizontal mitochondrial transfer, HMT—by means of tunnelling nanotubes or other mechanisms does not pertain just to cancer cells. Tunnelling nanotubes were first described in vitro in 2004. Subsequently, tunnelling nanotubes were shown to be “highways” for horizontal transfer of various cell contents, from ions to pathogens and even organelles, including mitochondria. Horizontal mitochondrial transfer then gained the interest of many, as HMT is not restricted to cancer cells or cells grown in vitro. Rather, it occurs naturally between many cell types, and it is involved in regeneration, homeostasis maintenance, and other medically important processes. The authors of the review—who themselves study HMT—thus provide a comprehensive overview of our knowledge of HMT and its practical applications.
The ability to participate in HMT is currently known from multiple cell types. HMT may occur between cells of the same cell type or between different cell types in response to stress or damage, as has been already described from lung tissue, myocardial muscle, kidney, or brain. In extreme cases, HMT may occur between different individuals—such is the case of canine transmissible venereal tumour, CTVT. Cells of this transmissible tumour utilise HMT to acquire healthy mitochondria from their dog host after their own mitochondria have been irreversibly damaged.
Besides stress or damage, HMT also occurs during normal physiological processes. HMT of healthy cells into neurons in the central nervous system helps maintain homeostasis of the cells and tissue. HMT from platelets into neutrophils may elicit an immune response. Moreover, the differentiation of mouse oocytes is facilitated by horizontal transfer of mitochondria and other organelles from surrounding germ cells. This list of functions is by no means exhaustive.
The review further documents the various mechanisms by which HMT may occur (Fig. 2). Besides the aforementioned nanotubes, mitochondria can be transferred through gap junctions or through cytoplasmic bridges arising through fusion of adjacent cells. However, HMT is possible even without direct cell contact—mitochondria may be transported through extracellular vesicles pinching off from cells and then fusing with (usually) nearby cells. Such extracellular vesicles facilitate the transport of damaged mitochondria from cardiomyocytes to macrophages for degradation. Furthermore, extracellular vesicles may be involved in interorgan transport of mitochondria. In obese patients, vesicles containing damaged mitochondria from adipocytes are transferred via blood circulation into heart tissue. There the mitochondria trigger compensatory antioxidant signalling.
Acquiring healthy mitochondria through HMT generally improves cell viability and resistance. Healthwise, this is a “double-edged sword”, as the authors themselves stress. In normal cells and tissues, HMT confers improved viability, homeostasis maintenance, or regeneration. However, it also allows cancer cells to survive and improves their resistance to apoptosis induced by chemotherapy or radiotherapy.
HMT is thus highly desirable in treating injuries and non-cancerous pathologies. The therapeutic potential of HMT was first explored in cardiac tissue recovering from ischemia/reperfusion injury. Injecting mitochondria from healthy cardiomyocytes into an ischemic area of rabbit hearts enhanced both functional recovery and cell viability. Similarly, the positive effect of HMT was demonstrated in CNS and retina following injury or various neurodegenerative disorders, including Parkinson’s disease. Moreover, HMT is involved in regeneration of lung injury, asthma, and improvement of immune system function.
On the other hand, HMT should be curbed in cancer therapy to prevent cancer cells from discarding damaged mitochondria and acquiring healthy mitochondria from surrounding cells. HMT can be prevented, for example, through disruption of the cytoskeleton necessary for nanotube function. This particular approach was successfully utilised in preventing HMT into leukaemia cells, and thus preventing chemotherapy resistance.
Further studies of HMT will no doubt offer not only new insights into previously overlooked physiological roles of mitochondria, but it may also offer therapeutic solutions for currently hard-to-treat injuries and diseases.
Dong, L. F., Rohlena, J., Zobalova, R., Nahacka, Z., Rodriguez, A. M., Berridge, M. V., & Neuzil, J. (2023). Mitochondria on the move: Horizontal mitochondrial transfer in disease and health. Journal of Cell Biology, 222(3), e202211044.