ADDRESSING MITOCHONDRIAL DYNAMICS IN INTERCELLULAR TRANSFER TO GLIOBLASTOMA

Glioblastoma multiforme (GBM) is a recurrent central nervous system cancer with a poor prognosis that remains incurable, primarily due to its resistance to the limited range of available therapies. Mitochondrial function and dynamics stand behind GBM progression, with regulators of shape and dynamics as major determinants. These dynamics result from the balance of fission events, mastered by Drp1 and fusion events tightly regulated by Mitofusins (Mfn1/Mfn2) and Opa1, as key players in the outer and inner mitochondrial membranes, respectively. However, little is known about the regulation of dynamics in the intercellular transfer of these organelles between neural and GBM cells, that ultimately reconfigure mitochondrial content and metabolism in GBM that primes tumor development.
Here, we advance the assessment and impact of mitochondrial DNA (mtDNA) acquisition, implemented with novel morphometry and dynamic tracking of intact mitochondria by GBM, to evaluate the import of free mitochondria from the extracellular medium, or the transfer through intercellular membranous bridges termed tunneling nanotubes (TNTs). Capitalizing on genetic and pharmacologic manipulations of mitochondrial shaping proteins, we show that concomitant or time-delayed interference with fusion and fission impacts the acquisition of astrocytic mitochondria by GBM. These events are underscored by changes in mtDNA loads and overall mitochondrial morphology. In sum, we provide evidence for the regulation of mitochondrial transfer by key players in fusion and fission, representing a novel therapeutic approach to interfere with GBM reconfiguration and progression.