**6. Mitochondria and multiple sclerosis**

**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

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

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

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

from the mitochondrial matrix space [22].

phosphorylation, and fatty acid breakdown pathways.

158 Trending Topics in Multiple Sclerosis

coupled to vectorial transport of H+

complexes is given by NADH or FADH2 [20].

In acute phases of the disease, axonal degeneration correlates with the severity of inflamma‐ tion. This type of injury has been used in an experimental model of autoimmune encephalo‐ myelitis (EAE), where acute mitochondrial damage within axons is detected and later suffers from focal damage as a preliminary pathological step of axonal damage [15].

Complex IV of the mitochondrial electron transport chain has a binding site for O2 (The final acceptor in the respiratory chain) and catalyzes the reduction in O2 to H2O. Interestingly, nitric oxide inhibits mitochondrial respiration by reacting with either the reduced or the oxidized binuclear site of cytochrome c oxidase, leading to ATP depletion. In cases of excessive nitric oxide production, complete inhibition of cytochrome c oxidase has been shown to contribute to pathology.

**Figure 8.** Association of mitochondrial electron transport chain with oxidative stress. The mitochondrial electron trans‐ port chain (ETC), which is composed of four multiprotein complexes named complex I–IV, has been recognized as one of the major cellular generators of free radicals. Leakage of electrons directly from the intermediate electron carriers generates reactive oxygen species that leads to membrane lipid peroxidation, mitochondrial DNA damage, and the re‐ lease of cytochrome C to the cytosol triggering apoptosis.

At the same time, interrupting the electron transport chain by binding of NO to complex IV increases electron release, thus facilitating the formation of reactive oxygen species, firstly superoxide anion and subsequently H2O2 and OH.. Peroxynitrite has a direct effect on mito‐ chondria leading to lipid peroxidation of membrane lipids and thus damaging the complexes of the respiratory chain and mitochondrial DNA. Opening of permeability transition pores and release of cytochrome C from mitochondria initiate apoptosis (**Figure 8**).

At the stage of acute inflammation, a set of mechanisms that alter mitochondrial function is produced. The energy deficit causes structural and functional damage to macromolecules by increased ROS that ultimately leads to severe axonal damage. In these events, the mitochondria has an important role; therefore, if we know what the mechanisms involved in glial and neuronal alterations are, we must be able to identify the elements that can be used as effector elements and design drugs to control and reduced harm during the stage of relapse [14].

Many demyelinated axons survive during a relapse, and these can become chronically demyelinated axons, in which case axonal mitochondria develop compensatory mechanisms to cope with the lack of myelin. There are reports in which inactive lesions from chronic demyelinated axons of patients with MS are observed. In such reports, they have found an increase in the activity of mitochondrial complex IV and increased synphilin anchoring protein [19]. However, axons progressively degenerate in chronic lesions of MS patients. In the absence of myelin, redistribution of Na+ occurs to maintain the transmission of nerve impulses that increases energy demand, and this produces a situation of "virtual hypoxia." At the end, the demand exceeds the capacity of axonal mitochondria to produce enough ATP, which causes an increase in the concentration of Ca2+ in the axon. Ca2+ pumping and extended levels of intramitochondrial calcium leads to opening pores, rupture of the outer mitochondrial membrane, and release of cytochrome C, finally leading to apoptosis (**Figure 8**).

binuclear site of cytochrome c oxidase, leading to ATP depletion. In cases of excessive nitric oxide production, complete inhibition of cytochrome c oxidase has been shown to contribute

**Figure 8.** Association of mitochondrial electron transport chain with oxidative stress. The mitochondrial electron trans‐ port chain (ETC), which is composed of four multiprotein complexes named complex I–IV, has been recognized as one of the major cellular generators of free radicals. Leakage of electrons directly from the intermediate electron carriers generates reactive oxygen species that leads to membrane lipid peroxidation, mitochondrial DNA damage, and the re‐

At the same time, interrupting the electron transport chain by binding of NO to complex IV increases electron release, thus facilitating the formation of reactive oxygen species, firstly

chondria leading to lipid peroxidation of membrane lipids and thus damaging the complexes of the respiratory chain and mitochondrial DNA. Opening of permeability transition pores

At the stage of acute inflammation, a set of mechanisms that alter mitochondrial function is produced. The energy deficit causes structural and functional damage to macromolecules by increased ROS that ultimately leads to severe axonal damage. In these events, the mitochondria has an important role; therefore, if we know what the mechanisms involved in glial and neuronal alterations are, we must be able to identify the elements that can be used as effector elements and design drugs to control and reduced harm during the stage of relapse [14].

Many demyelinated axons survive during a relapse, and these can become chronically demyelinated axons, in which case axonal mitochondria develop compensatory mechanisms to cope with the lack of myelin. There are reports in which inactive lesions from chronic demyelinated axons of patients with MS are observed. In such reports, they have found an increase in the activity of mitochondrial complex IV and increased synphilin anchoring protein [19]. However, axons progressively degenerate in chronic lesions of MS patients. In the absence

occurs to maintain the transmission of nerve impulses that

and release of cytochrome C from mitochondria initiate apoptosis (**Figure 8**).

Peroxynitrite has a direct effect on mito‐

lease of cytochrome C to the cytosol triggering apoptosis.

of myelin, redistribution of Na+

superoxide anion and subsequently H2O2 and OH..

to pathology.

160 Trending Topics in Multiple Sclerosis

One of the questions we have not answered is: Why are mitochondria helpless and over‐ whelmed by the energy demand and how does this happen? Are the axons unable to maintain stable mitochondrial activity in demyelination?. This reflects the inability of the cell to carry and generate mitochondria. Dutta et al. [23] have shown decreased gene expression of 26 nuclear‐encoded subunits of the oxidative phosphorylation chain in non‐demyelinated motor cortex from MS patients, which coincided with a significant reduction in activity of NADH dehydrogenase and ubiquinol‐cytochrome c reductase . In the progressive phase of MS, it is postulated that chronically demyelinated axons are unable to maintain mitochondrial func‐ tion, and thus, a deficit of ATP synthesis coupled with oxidative stress results in irreversible axonal damage.
