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We have previously shown the role of this process in the adaptation of poly(morpho)nuclear \u201cgiant\u201d cells (PGCs) in T98G populations to doxorubicin (DOX)-induced stress. Here, we addressed the role of a \u201cresistance triad\u201d, which coordinates metabolic T98G reprogramming with the activation of the drug-relocation and drug-retention axis, in the recovery of GBM populations from chemotherapeutic stress. A combination of proteomic analyses with metabolic and phenotypic profiling of pulse DOX-treated T98G cells revealed the significance of mitochondrial dynamics for the efficiency of the T98G \u201cresistance triad\u201d. DOX-induced mobilization of ATP-generating systems and ATP-dependent anabolic pathways was accompanied by the formation of DOX-negative, \u201cmosaic\u201d mitochondrial networks and the upregulation of mitofusin-2 (MFN2) in T98G PGCs. Transient MFN2 down-regulation correlated with the respiratory capacity of T98G cells, while impairing cell welfare in the absence and presence of DOX. However, minute fractions of PGCs, which withstood combined MFN2 down-regulation and pulse DOX treatment, retained mitochondrial networks and displayed efficient ABC transporter-\/V-type channel-dependent lysosomal DOX retention. Collectively, a \u201ctriad\u201d of mitochondrial activation, ABC transporter-dependent perinuclear redistribution and V-type channel-mediated lysosomal DOX compartmentalization determines DOX resistance of T98G cells. Whereas MFN2-dependent mitochondrial rearrangements may contribute to these processes, complementary adaptative mechanisms can compensate MFN2 dysfunction, limiting its potential as a therapeutic target.<\/jats:p>","DOI":"10.3390\/cells15100899","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Dynamics Participate in an Early Metabolic Adaptation of Glioblastoma Multiforme T98G Cells to Doxorubicin-Induced Chemotherapeutic Stress"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1893-3066","authenticated-orcid":false,"given":"Maciej","family":"Pude\u0142ek","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksym","family":"Pude\u0142ek","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Przenios\u0142o","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"K\u0119dracka-Krok","sequence":"additional","affiliation":[{"name":"Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew","family":"Madeja","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6779-7630","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Czy\u017c","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","unstructured":"Kanderi, T., Munakomi, S., and Gupta, V. 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