**6.1. Mitochondrial network**

Ultrastructurally, mitochondrion is an organelle constituted by a peripheral and inner membrane. The peripheral membrane encloses the entire contents of the mitochondrion, and internal membrane forms a series of folds, called cristae, which project inward toward the interior space of the organelle. The area between the peripheral and inner membranes is designated as intermembrane space, and the area enclosed by the internal membrane is labeled as a mitochondrial matrix. Functionally, the outer membrane includes the apoptosis antagonists and agonists and fission/fusion mitochondrial proteins. The inner membrane contains all the respiratory enzyme complexes and the three electron transporters, necessary for oxidative phosphorylation. In major mammalian tissues, 80–90% of ATP is generated by mitochondria in the process of oxidative phosphorylation [17, 18]. The mitochondrial matrix contains the enzymatic system of β-oxidation and tricarboxylic acid cycle. Mitochondria in living human cells display large, elongated and branched structures, actually entitled as mitochondrial network, extending throughout the cytosol and in close contact with the nucleus, the endoplasmic reticulum, the Golgi complex and the cytoskeleton, and is continually remodeled by both fusion and fission events [19].

In some cell types, mitochondria exist as single and randomly dispersed organelles; in other cells, mitochondria may also exit as dynamic networks that often changes shape and subcellular distribution. Depending on the cell type, mitochondria localized in different site-specific regions of a cell may display dissimilar morphology and biochemical properties [20].

(an area with high density of MAM and predicted the functional activity). Close or direct association (mitochondria-endoplasmic reticulum interface <30 nm) and detached or disrupted (>30 nm) associations is present. The shortest span of MAM was 96 nm, and the

**Figure 3.** (A–C) Glioblastoma cells displays variable organization of endoplasmic reticulum membrane associated with mitochondria (circles, ellipses, and arrows). M/m denotes mitochondria; er: endoplasmic reticulum profiles. N: cellular nucleus. Lucent-swelling mitochondria with disarrangement and distortion of cristae, and partial or total cristolysis,

Functional and Therapeutic Implications of Mitochondrial Network and Mitochondria…

http://dx.doi.org/10.5772/intechopen.77224

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In the ultrastructural perspective, we identified two remarkable cell types: (1) poorly differentiated glioma stem cells and (2) well-differentiated glioma cells. The first one exhibits a poorly developed mitochondrial network and scarce MAM (named by us "MAM-deficient cells"). The second contains a well-developed MN and numerous MAM (named by us "MAMenriched cells"). MAM displayed a network or "work station" in some well-differentiated

Previously, we suggest that the MAM could be involved in the invasive properties of glioma cells. Human glioma cell invadopodia show mitochondria with a dense matrix condensed configuration, indicating an active state. The mitochondria were frequently in close contact with an extended smooth endoplasmic reticulum displaying an endoplasmic reticulum subfraction associated with mitochondria MAM. Fluorescent microscopy confirmed that D54 and U251 glioma cells growing in vitro also contained filopodia with mitochondria (**Figure 5**). The U251 glioma cells' filopodia that penetrated through 1.2-μm pores of transwell chambers also contained mitochondria, suggesting that the mitochondria are actively involved in the

In the vascular microenvironment components of gliomas, the mitochondrial network exhibit similar changes to describe in tumoral cells. The mitochondria display mainly two patterns: (1) swelling associated with disarrangement of cristae and partial or total cristolysis and (2)

longest was 652 nm [10].

are seen.

glioma cells [10] (**Figure 4**).

invasion process [9].

condensed configuration [8].

### **6.2. Mitochondria-associated membranes**

MAM is a membranous and protein structure (inter-membranous structure) composed by three pieces: (1) endoplasmic reticulum membrane; (2) mitochondrial membrane (outer mitochondrial membrane); and (3) tethers (proteins). Consequently, it displays biological membranous processes such as molecules trafficking and signaling events.

To date, MAM is considered as a fundamental cellular structure tightly regulated and with multifaceted roles that include Ca2+ signaling, lipid synthesis and exchange, metabolic control, and others. MAM formation might depend on several factors relating to differences in cell demands or microenvironment stimuli [2, 21].
