**7. Conclusions**

showed that glioma stem cells are less glycolytic than differentiated glioma cells, consuming lower levels of glucose, and producing lower amounts of lactate while maintaining higher ATP levels compared with their differentiated progeny [26]. Another study, by means of transmission electron microscopy, analysis revealed that the number of mitochondria with distinct cristae and electron-dense matrices increased significantly in the non-stem differentiated glioma cells when compared to their undifferentiated glioma stem cells. The final conclusion was that glioma stem cells prefer a relatively higher glucose metabolism, which implies that they utilize different mitochondrial biosynthesis and metabolic pathways when compared to differentiated glioma cells [27]. Other research established that glioma stem cells displayed diminished endoplasmic reticulum-mitochondria contacts compared to glioma differentiated cells. Forced endoplasmic reticulum-mitochondria contacts in glioma stem cells increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. The final conclusion was that endoplasmic reticulum-mitochondria contacts control surface glycan

The length of the interface is changing under different biochemical conditions [29, 30]. Apparently, the execution of the physiological programs is dependent on the length of the MAM, since the structural plasticity of the MAM cleft accompanies changes in cell metabolism [29]. Changing the thickness of MAM would impact on the activity of several enzymes of the Krebs cycle and on the strength of the IP3R Ca2+ signaling pathway [30]. Furthermore, the variability of the ultrastructural aspects observed on astrocytic tumors suggests a dynamic regulation of the interorganellar junction that can be modified by functional requirements needed to adapt to different cell demands. Solid and glycolytic tumor tissue is frequently characterized by a loss of normal MAM architecture and formation [6]. Today, altered Ca2+ signaling at the MAM is recognized as a hallmark of cancer cells that shifts their metabolism to glycolysis and increases their resistance to cell death [31]. MAM-resident mTORC2 controls the MAM integrity and mitochondrial functions [4, 32] and is the core of MAM signaling hub that controls growth and metabolism. Recent studies suggest that mTORC2 can promote glioblastoma growth and chemotherapy resistance in cancer cells as well as controlling genome stability and tumor metabolism including glycolysis, glutaminolysis, lipogenesis, and nucleotide and reactive oxygen species metabolism [33]. Glucose is required to activate mTORC2 and promote tumor growth [33] by means an auto-activation loop of mTORC2, rendering glioblastoma resistant to EGFR, PI3K, or AKT-targeted therapies. Then, if sufficient nutrients are present, glioblastoma cells maintain mTORC2 signaling to drive cell proliferation, and survival [33, 34]. mTOCR2 markedly increases glycolysis in glioblastoma [33]. Consequently, replacement of fermentable fuels like glucose and glutamine with nonfermentable fuels like ketone bodies becomes a logical approach to management [35, 36]. The dietary intervention prevents glioma cells accessing their preferred fuel source, i.e., glucose [37–40], and consequently, the signal transduction of mTORC2, cell proliferation and survival are diminished [35]. Therefore, impairments in glucose availability can be devastating for

The current standard of care for glioblastoma patients consists of maximal safe resection, followed by radiotherapy, and concurrent chemotherapy with Temozolomide [15, 41, 42]. Despite substantial clinical research efforts over the past decades, therapeutic progress

expression and sensitivity to killer lymphocytes in glioma stem-like cells [28].

22 Glioma - Contemporary Diagnostic and Therapeutic Approaches

glioma survival [26].

There is a great need to develop new therapies for gliomas. The ultrastructural findings observed in MN and MAM in the human gliomas indicate that: (1) The majority of glioma cells are incompetent to produce adequate amount of energy by means of oxidative phosphorylation and compensatory increases in glycolytic ATP production and (2) The variability of the ultrastructural aspects of MAM observed on astrocytic tumors suggests a dynamic regulation of the interorganellar junction that can be modified by functional requirements needed to adapt to different cell demands. These findings possibly represent the ultrastructural basis of the metabolic processes of glioma cells. MAM-resident mTORC2 controls the MAM integrity and mitochondrial functions, and mTORC2 can promote growth and chemotherapy resistance in cancer cells as well as tumor metabolism including glycolysis, glutaminolysis,

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**Figure 6.** General visualization of the glioma pathology, metabolic aspects and, their metabolic therapy approach. Glucose derived from extracellular nutrients is required to activate mTORC2 and promote tumor growth and resistance. Glucose is converted in acetyl-CoA for the pyruvate deshydrogenase (PDH) action. Acetyl-CoA produces the activation of mTORC2 by acetylation of RICTOR. mTORC2 signaling facilitates the metabolic reprogramming, tumor growth, and resistance. This is a nutrient availability-dependent process, by means an auto-activation loop of mTORC2. The metabolic therapy approach, limit the availability of glucose and consequently, the signal transduction of mTORC2, cell proliferation, and survival are diminished (ellipse denotes MAM).

lipogenesis, and nucleotide and reactive oxygen species metabolism. Considering that therapeutic progress has been marginal, ketogenic metabolic therapy in the context of the presspulse therapeutic strategy is emerging as a potential therapeutic option (**Figure 6**).
