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Introduction: Mitochondrial DNA (mtDNA) content in several solid tumors was found to be lower than in their normal counterparts. However, there is paucity of literature on the clinical significance of mtDNA content in glioblastoma and its effect on treatment response. Hence, we studied the prognostic significance of mtDNA content in glioblastoma tumor tissue and the effect of mtDNA depletion in glioblastoma cells on response to treatment., Materials and Methods: 130 newly diagnosed glioblastomas, 32 paired newly diagnosed and recurrent glioblastomas and 35 non-neoplastic brain tissues were utilized for the study. mtDNA content in the patient tumor tissue was assessed and compared with known biomarkers and patient survival. mtDNA was chemically depleted in malignant glioma cell lines, U87, LN229. The biology and treatment response of parent and depleted cells were compared., Results: Lower range of mtDNA copy number in glioblastoma was associated with poor overall survival (p = 0.01), progression free survival (p = 0.04) and also with wild type IDH (p = 0.02). In recurrent glioblastoma, mtDNA copy number was higher than newly diagnosed glioblastoma in the patients who received RT (p = 0.01). mtDNA depleted U87 and LN229 cells showed higher survival fraction post radiation exposure when compared to parent lines. The IC50 of TMZ was also higher for mtDNA depleted U87 and LN229 cells. The depleted cells formed more neurospheres than their parent counterparts, thus showing increased stemness of mtDNA depleted cells., Conclusion: Low mtDNA copy number in glioblastoma is associated with poor patient survival and treatment resistance in cell lines possibly by impacting stemness of the glioblastoma cells., (Copyright © 2020. Published by Elsevier B.V.)