由于胶质母细胞瘤（GBM）的高度复杂性，治疗极具挑战性。它是一种已明确鉴定出高耐药性神经胶质瘤起始细胞 (GIC) 亚群的肿瘤。因此，了解 GIC 和肿瘤细胞之间的差异对于转向不太传统但更有效的方法至关重要。研究发现，与其分化的后代不同，GIC 的存活和干细胞特性的维持依赖于线粒体代谢。 GIC 表现出更高的葡萄糖摄取和线粒体膜电位，并降低乳酸脱氢酶活性，比其分化的对应物对线粒体抑制更敏感。流向线粒体的钙流似乎在维持这种独特的代谢表型中发挥着重要作用，电压依赖性阴离子通道 (VDAC) 和 Grp75（IP3R-Grp75-VDAC 复合物中的两种蛋白质）的表达减少。将钙从内质网 (ER) 转移到线粒体。使用 ER 应激诱导剂破坏 ER 稳态或使用 Grp75 抑制剂 MKT-077 抑制 ER 线粒体接触位点，会导致 GIC 的细胞毒性和干性丧失。此外，MKT-077 还增强了替莫唑胺（目前治疗胶质母细胞瘤的药物）的效果。总之，目前的数据表明 ER 线粒体稳态对于 GIC 葡萄糖代谢和生存的调节至关重要。

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.