MIRO1, A KEY ACTOR IN THE REGULATION OF MITOCHONDRIAL TRANSFER TO GLIOBLASTOMA CELLS

Glioblastoma (GBM) is the most common and lethal glioma, due to its high ability for tissue infiltration and chemoresistance. Recent discoveries reveal that GBM cells form tunneling nanotubes (TNTs) that communicate with surrounding neural cells, promoting GBM infiltration and tumor progression. TNTs enable GBM cells to establish coordinated networks and communications, ranging from intercellular signaling to the sharing of intact and functional mitochondria. The dynamics of mitochondrial transfer require active transport mediated by the motor adaptor Miro1, which is critical for the anterograde movement of organelles to the periphery of the donor cells. The role of Miro1 in mitochondria transfer and integration intro GBM cells, however, is still scarcely known.
Here, we evaluate mitochondrial transfer from donor neural cells to GBM cells, both in vitro and in vivo. Our results indicate that Miro1 is critical in this process, as it is required for mitochondrial transfer through TNTs. Capitalizing on genetic and pharmacological approaches, we show that Miro1 downregulation significantly impaired mitochondrial transfer from donor cells to GBM cells via TNTs, at the expense of changes in the acquisition of free mitochondria. Upstream of Miro1, interfering with actin and tubulin polymerization and thus mitochondrial interactions with the cytoskeleton extensively disrupts mitochondrial transfer to GBM cells, as confirmed by microscopy and flow cytometry.
Together, these findings highlight the importance of Miro1–cytoskeleton interactions in regulating mitochondrial transfer, supporting the impact of transfer as primers of GBM tumor progression and placing it as a key therapeutic target to limit GBM development.