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Glioblastoma (GBM) treatment is extremely challenging due to the high complexity of the tumor. It is one of the tumors in which a subpopulation of highly resistant glioma initiating cells (GICs) has been clearly identified. Thus, understanding the differences between GICs and tumor bulk cells is therefore essential to move to less conventional but more efficient approaches. It was found that, unlike their differentiated progeny, GICs survival and maintenance of stem cell properties depend on mitochondrial metabolism. GICs present higher glucose uptake and mitochondrial membrane potential and reduced lactate dehydrogenase activity, being more sensitive to mitochondrial inhibition than their differentiated counterparts. Calcium flux to the mitochondria appears to play an essential role in the maintenance of this distinct metabolic phenotype with a decrease in the expression of voltage‑dependent anionic channel (VDAC) and Grp75, two of the proteins of the IP3R‑Grp75‑VDAC complex that transfers calcium from the endoplasmic reticulum (ER) to the mitochondria. Disruption of ER homeostasis using ER stress inducers or inhibition of ER‑mitochondrial contact sites using the Grp75 inhibitor MKT‑077 resulted in cytotoxicity of GICs and loss of stemness. Moreover, MKT‑077 also potentiates the effect of temozolomide, current treatment for glioblastoma. In summary, the present data indicated that ER‑mitochondrial homeostasis is essential for regulation of GICs glucose metabolism and survival.