**5. Mitochondria**

**4.1. Glutathione deficiency and multiple sclerosis**

156 Trending Topics in Multiple Sclerosis

omega‐6 fatty acids) [17].

used to draw the figure [27].

There are several reports in the literature that relate the decrease or alteration of glutathione (GSH) metabolism with several neurodegenerative diseases. Biochemical analysis of postmor‐ tem brains has provided evidence for the generation of oxidative stress during the course of the disease since the total GSH content is reduced by 40–50% compared to controls. Also in several brain regions, we have found increased levels of lipid peroxidation [17]. The ratio GSH/ GSSG (usually 10:1) is considered consistent with the concept of oxidative stress as an important part in the pathogenesis of MS. Moreover, low concentrations of GSH appear to be an important indicator of oxidative stress during the progression of MS. Although the decrease in GSH alone is not responsible for the degeneration of glial cells and neurons, reduced GSH could increase the susceptibility to other stressful factors and contribute to neuronal damage at glia and neuron cells. Glutathione has been reported to protect mitochondrial complex I activity against nitrosative stress, as S‐nitrosoglutathione is formed. When this complex increases its content of nitrotyrosine and nitrosothiol groups in response to nitrosative stress, its activity is inhibited and therefore ATP production is diminished, which causes neuronal degeneration [10]. The role of glial cells in generating ROS in MS and the selective vulnerability of neurons is due to activated glial cells surrounding these neurons, as these glial cells are also directly involved in GSH levels. The engagement of the glutathione system in astroglial cells contributes to the reduction in its antioxidant defenses and so poor glial defense could contribute to existing neuronal damage (**Figure 5**) [10]. Furthermore, the specific activities of some enzymes that metabolize GSH are high, as in the case of glutathione peroxidase, glutathione reductase, and glutathione S‐transferase. Other products of OS are also elevated, as in the case of 4‐hydroxynonenal (4‐HNE, a product of lipid peroxidation of polyunsaturated

**Figure 5.** Genetic defect in glutathione synthesis and neurodegenerative diseases. Pathway Builder Online Tool was

Mitochondria are granular and filamentous organelles found in the cytoplasm of all eukaryotic cells and are the main site of adenosine triphosphate (ATP) synthesis by the processes of oxidative phosphorylation. These organelles vary in size and shape depending on the source and metabolic status, but are often ellipsoids of about 5 microns in diameter and 1 micron long. A typical eukaryotic cell contains more than 2,000 mitochondria, which takes up about one‐ fifth of the cell volume, an amount that is needed to meet the energy demands of the cell. Its main function is the mitochondrial respiration process in which the reducing power produced in the oxidation reactions enters the electron transport chain and energy is captured in the form of adenosine triphosphate (ATP). Mammalian tissues containing more mitochondria are the heart and brain [19]. The mitochondrion is formed by two membranes: the outer membrane and the inner membrane, which is highly folded, and the inner matrix is gel (approximately 50% water) [20].

The outer mitochondrial membrane contains porin, a pore‐forming protein that allows diffusion of up to 10 kD molecules). The inner membrane contains approximately 75% protein and 25% lipids by weight, and it is much richer in outer membrane proteins. The inner membrane is permeable only to carbon dioxide (CO2), oxygen (O2), and water (H2O). The passage of metabolites such as ATP, adenosine diphosphate (ADP), pyruvate, calcium ions (Ca2+), and phosphate (PO4) is regulated by controlling the transport proteins. This controlled permeability allows the generation of ionic gradients and results in the compartmentalization of metabolic functions between the cytoplasm and mitochondria. The inner membrane components of the respiratory chain are responsible for the synthesis of ATP (ATP synthase FoF1) [22], where the enzyme complex is housed. The inner membrane is arranged in ridges, giving it a large surface area: A single mitochondrion may have more than 10,000 sets of electron transfer systems (respiratory chain) and ATP synthase molecules distributed through‐ out the membrane's internal surface [21]. The inner membrane is, from the functional point of view, the most important because it contains the components of the respiratory chain and proteins necessary for the synthesis of ATP [21]. The mitochondrial matrix is the space delimited by the inner membrane and contains the pyruvate dehydrogenase complex and the enzymes of the tricarboxylic acid cycle (TCA), the fatty acid oxidation, and the oxidation of amino acids [21] (**Figure 6**).

**Figure 6.** Main mitochondrial metabolic pathways. An important component of metabolic regulation is specialization. Mitochondria have a role in biosynthesis, catabolism, and energy metabolism, including citric acid cycle, oxidative phosphorylation, and fatty acid breakdown pathways.

The chemical energy required for cellular activities such as biosynthesis, transportation of ions and molecules, and mechanical work comes from ATP. Mitochondria generate more than 90% of the energy needed for the proper functioning of tissues that are highly dependent on aerobic metabolism, such as the brain and heart. This subcellular organelle provides the energy necessary for the production of ATP [22]. Depending on cell type and metabolic state, mito‐ chondria consume approximately 90–95% of the oxygen consumed by the cell. The energy of this process, in which electrons are transferred from the substrates of the TCA to oxygen, is coupled to vectorial transport of H+ from the mitochondrial matrix space [22].

The electron carriers, reduced nicotinamide dinucleotide adenine (NADH) and reduced flavin dinucleotide adenine (FADH2), originating mainly in the TCA cycle, confer the energy that electrons carry. This energy is released gradually along the respiratory chain in the mitochon‐ drial inner membrane. In this membrane, an exchange of electrons between the enzymatic complexes is given by NADH or FADH2 [20].

The complexes are as follows: I (NADH‐ubiquinone reductase), II (succinate‐ubiquinone reductase), III (ubiquinol‐cytochrome c reductase), IV (cytochrome oxidase), and V (ATP synthase complex FoF1) [20]. Electron transport is carried out by complexes I, III, and IV that produce a flow of electrons accompanied by a movement of protons from the mitochondrial matrix to the intermembrane space (space between the inner and outer mitochondrial mem‐ brane). This produces a difference in proton concentration and a difference in charge across the membrane [20]. The proton‐motive force generated thereby drives protons through the F0F1‐ATP synthase, allowing condensation of a phosphate group to ADP, with the formation of ATP [23]. Meanwhile, the complex F0F1‐ATP synthase is an enzyme located in the inner membrane of the mitochondria, responsible for ATP synthesis from ADP and a phosphate group (Pi), and the energy is supplied by a flow of protons (H<sup>+</sup> ). The difference between the terms ATPase and ATP synthase is that the enzyme has a dual function: It breaks down ATP to ADP and Pi (activated ATPase), and it also allows for catalyzing Pi binding of ADP using the proton gradient for ATP synthesis (ATP synthase activity). As complex V has both functions, we can name it indiscriminately when speaking in general terms of the enzyme [23]. This enzyme is constituted by two components: a soluble portion (F1), located in aqueous medium, and another portion (Fo), which is lipid soluble. The F<sup>o</sup> part is inserted into the lipid bilayer and is sensitive to the antibiotic oligomycin (**Figure 7**).

**Figure 7.** ATP synthase complex structure. The ATP synthase complex plays a central role in energy transduction in living cells that uses energy released by the movement of protons down a transmembrane electrochemical gradient to drive the synthesis of ATP. This enzyme is located in the inner membrane of mitochondria and is constituted by two parts: a soluble portion (F1) in aqueous medium and another portion (Fo) lipid soluble. The Fo part is inserted into the lipid bilayer.

On the other hand, pathophysiological features exhibited the association between mitochon‐ drial dysfunction, decreased activity of complex I and complex IV of the electron transport chain, and the glutathione system in MS [23].
