**1. Introduction**

The word apoptosis has its etymological origin in the Greek *apó,* which means "from" and *ptōsis* which means "falling off." The merging of these two words is an allusion to the natural events of shedding cells and tissues, as well as the falling of old leaves during autumn. Apoptosis describes the process in which unwanted, damaged, or old cells are eliminated in multicellular organisms [1], which is necessary in all body tissues and happens naturally during

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

embryogenesis, metamorphosis, and constant cellular changes, being of upmost importance for the maintenance of homeostasis in all tissues [2]. The term apoptosis was coined since 1972 by Kerr, to define a type of programmed cell death with morphological and molecular characteristics different from other types of cell death. These characteristics include retraction of pseudopods with the consequent reduction of cellular volume and rounding of the cell, nuclear volume reduction (pyknosis) and fragmentation (karyorrhexis), structural modification of organelles followed by the formation of vesicles due to blebbing of the plasma membrane [3, 4]. Apart from being a fundamental process of cells for the maintenance of homesostasis, apoptotic cell death represents an important defense mechanism against intracellular pathogens. Against it, a wide spectrum of microorganisms has developed diverse strategies to inhibit apoptosis of their host cells. These strategies involve different signaling pathways that are hijacked by pathogens to achieve their goal of inhibiting apoptosis and persist inside cells. The purpose of this chapter is to better understand the signaling pathways that are targeted by protozoan parasites in order to evade the defense mechanism of apoptosis.

*2.1.2. The intrinsic pathway*

**2.2. Caspases**

The mitochondrial intrinsic pathway can be initiated by different intracellular stimuli such as

Signaling Pathways Targeted by Protozoan Parasites to Inhibit Apoptosis

tive stress, among others [15]. In this pathway, a family of proteins called Bcl-2, characterized for having from 1 to 4 conserved domains that share homology with Bcl-2 or BH [6], has a leading role. This family is composed of proapoptotic proteins that, according to the BH domains that possess, are divided into Bax and "BH3 only" subfamilies. The members of the Bax subfamily are Bak, Bax, Bok, and Mtd and possess three BH domains (BH1-BH3), while the "BH3 only" subfamily, as denoted by its name, possesses a single BH3 domain and is composed of Bid, Bad, Bim, Bik, Blk, Hrk, NOXA or PUMA. On the other hand, the antiapoptotic proteins family present four BH domains (BH1-BH4) and is composed of Bcl-2, Bcl-XL, Bcl-W, Bfl-1, and Mcl-1 [6]. The BH1 and BH2 domains are structurally similar to the diphtheric toxin [25, 26]. The antiapoptotic proteins Bcl-2 and Bcl-xL are located in the outer mitochondrial membrane and prevent the release of cytochrome c, while the proapoptotic proteins Bad, Bid, Bax, and Bim are located in the cytosol and under certain stimuli are translocated to the mitochondria, where they induce the release of cytochrome c [25, 26]. Additionally, caspase 8 may take part in the intrinsic pathway through Bid proteolysis, turning it into tBid, which also translocates to the mitochondria and activates Bcl-2, Bax, and Bak [27]. Once Bax and Bak have been translocated to the mitochondrial membrane, a molecular complex referred to as PTPC is activated and induces the Mitochondrial Transition Permeability (MTP) phenomenon [28, 29]. These events culminate in the permeabilization of the outer mitochondrial membrane or MOMP, which is the rate-limiting step in apoptosis that conducts to an energetic and metabolic damage and the cell faces irreversible apoptotic cell death. The release of cytochrome c from the mitochondrion permits its association with the Apoptosis Activation Factor (Apaf-1) thus forming a structure to which procaspase 9 is incorporated, originating a molecular complex referred to as the apoptosome. As procaspase 9 is activated, it recruits executor caspases 3 and 7, which causes a proteolytic effect inducing cell death [27]. As mentioned earlier, the intrinsic pathway can also be activated via endoplasmic reticulum stress whose main stimulus is the misfolding of proteins and their subsequent accumulation in the endoplasmic reticulum (ER). Once mis-

folded proteins reach a critical concentration, they activate ER membrane sensors [30].

the cytoskeleton, while AIF and ENDOG can enzymatically attack DNA [31].

The induction of apoptosis conducts hopelessly to the activation of caspases; nevertheless, the damage to the mitochondria can, in some cases, provoke the release of some molecules with proapoptotic capacities such as HTRA2, AIF and ENDOG that have the ability to induce apoptosis without the intervention of caspases. HTRA2 has the ability to attack proteolytically

Caspases (**C**ysteine-dependent, **ASP**artate-specific peptid**ASE**) owe their name to the fact that their proteolytic functions lie specifically in an aspartate residue and require the presence of cysteine to perform their catalytic activity [6]. There are many types of caspases and are classified according to their function in initiation caspases: 2, 8, 9, and 10; executor caspases: 3, 6,

) concentration, oxida-

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irreversible genotoxic damage, increase in the cytoplasmic calcium (Ca+
