Functional and Therapeutic Implications of Mitochondrial Network and Mitochondria-Associated Membranes: The Glioma’s Case

Abstract

Even today, despite the surgery, radiotherapy, and chemotherapy, gliomas prognosis is still poor. There is a great need to develop new therapies. The understanding of the structural and functional characteristics of mitochondrial network (MN) and mitochondriaassociated membranes (MAM) in gliomas is essential for the design of future therapeutic strategies. A huge range of ultrastructural findings is observed in MN and MAM in the human gliomas. These findings imply that a majority of glioma cells are incompetent to produce an adequate amount of energy by means of oxidative phosphorylation and compensatory increases in glycolytic ATP production. Regarding MAM, a "MAM-rich" cell (well-differentiated glioma cells) and "MAM-deficient" cells (glioma like-stem cells) exist. The quantity of MAM could be linked to the functional or metabolic state of the different glioma cells. MAM-resident mTORC2 is a major regulator tumor growth and drug resistance. If sufficient nutrients are present, glioblastoma cells maintain mTORC2 signaling to drive cell proliferation and survival. Consequently, the replacement of fermentable fuels like glucose with non-fermentable fuels like ketone bodies becomes a logical approach. The vision must be targeting the cellular signaling pathways and metabolic reprogramming. Whatever the modality, a holistic and feasible approach must be developed.