The missing link: does tunnelling nanotube-based supercellularity provide a new understanding of chronic and lifestyle diseases?

Abstract

Tunnelling nanotubes (TNTs) are increasingly recognized as central players in a multitude of cellular mechanisms and diseases. Although their existence and functions in animal organisms are still elusive, emerging evidence suggests that they are involved in developmental processes, tissue regeneration, viral infections or pathogen transfer, stem cell differentiation, immune responses as well as initiation and progression of neurodegenerative disorders and cancer (see Sisakhtnezhad & Khosravi 2015 Eur. J. Cell Biol. 94, 429–443. (doi:10.1016/j.ejcb.2015.06.01010.1016/j.ejcb.2015.06.010)). A broader field of vision, including their striking functional and structural resemblance with nanotube-mediated phenomena found throughout the phylogenetic tree, from plants down to bacteria, points to a universal, conserved and tightly regulated mechanism of cellular assemblies. Based on our initial definition of TNTs as open-ended channels mediating membrane continuity between connected cells (Rustom et al. 2004 Science 303, 1007–1010. (doi:10.1126/science.109313310.1126/science.1093133)), it is suggested that animal tissues represent supercellular assemblies that—besides opening discrete communication pathways—balance diverse stress factors caused by pathological changes or fluctuating physiological and environmental conditions, such as oxidative stress or nutrient shortage. By combining current knowledge about nanotube formation, intercellular transfer and communication phenomena as well as associated molecular pathways, a model evolves, predicting that the linkage between reactive oxygen species, TNT-based supercellularity and the intercellular shuttling of materials will have significant impact on diverse body functions, such as cell survival, redox/metabolic homeostasis and mitochondrial heteroplasmy. It implies that TNTs are intimately linked to the physiological and pathological state of animal cells and represent a central joint element of diverse diseases, such as neurodegenerative disorders, diabetes or cancer.

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells

“…As this is not the case, the selective transfer of whole, intact mitochondria remains the only possible explanation of our experimental data. The next step will be to investigate the mechanism of mitochondrial trafficking between cells in vivo, with tunnelling nanotubes being a plausible mode of intercellular transfer of the organelles (Rustom et al, 2004; Rogers and Bhattacharya, 2014; Rustom, 2016). …”

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

“…This crosstalk is essential to disseminate signals and transfer cellular components, including metabolites and organelles, allowing a syncytial behaviour, not only in basal conditions, but also in response to external stimuli. Given the importance of a fine-tuned intercellular communication for the homeostasis of a healthy organism, its deregulation has been extensively associated with the development of several pathologies, such as cancer, cardiovascular diseases and age-related disorders (Aasen et al, 2016;Bang et al, 2015;Grek et al, 2014;López-Otín et al, 2013;Pitt et al, 2016;Rustom, 2016).…”

Inherited mitochondrial genomic instability and chemical exposures

“…Recent work by the same group have now demonstrated that horizontal mtDNA transfer from donor cells to mtDNA depleted cells enabled increased mitochondrial respiration, which was essential for these cells to form tumors (Berridge et al 2015; Dong et al 2017). These findings highlight new and exciting cellular mechanisms, such as nanotube transmission of mtDNA from one cell to another (Rogers and Bhattacharya 2013; Rustom 2016; Rustom et al 2004), that could be targeted to develop new and specific treatments of mitochondrial diseases.…”