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bioRxiv · 10.64898/2026.06.12.730900

Tunneling nanotubes mediate mitochondrial homeostasis in cancer

Saenz-de-Santa-Maria, I.·Pepe, A.·Brou, C.·Tinevez, J.·Vitrenko, Y.·Cokelaer, T.·Moyal, E.·Weigert, R.·Zurzolo, C.
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Abstract

Tumor progression is driven by cancer cells ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the effects of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. In this study, we demonstrate bidirectional mitochondrial transfer: damaged mitochondria from Glioblastoma (GBM) cells trigger mitophagy in non-tumoral astrocytes (AS), while healthy mitochondria from AS enhance the metabolic activity of GBM cells. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model, allowed the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings provide critical insights into TME interactions and their contribution to cancer resilience, highlighting TNTs as a potential target for therapeutic intervention and paving the way for further research into their role in cancer.

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Saenz-de-Santa-Maria, I., Pepe, A., Brou, C., Tinevez, J., Vitrenko, Y., Cokelaer, T., Moyal, E., Weigert, R., Zurzolo, C.. 2026-06-15. Tunneling nanotubes mediate mitochondrial homeostasis in cancer. https://doi.org/10.64898/2026.06.12.730900

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