3.1.1. Body Wall (Tegument)

The parasitic flatworms of the Neodermata group have a glycocalyx rich in carbohydrates in their external part of the membrane that limits the tegument, which consists of a simple syncytium that covers the entire surface of these worms [44]. However, this tissue results from the fusion of cytoplasmic projections of parenchymal cells (also known as cytones) that are found below the basement membrane and whose function is to provide

a constant flow of proteins and other molecules to the tegument [45] (Figure 3). Ultrastructural adaptations can be present such as microtriches in the case of cestodes, which increase the surface area of the parasite allowing a greater exchange between it and the host, as well as recognition mechanisms through the glycocalyx [46].

**Figure 3.** Tegument of the cestodes. Panel (**a**) represents a photograph of the tegument of *Taenia crassiceps* cysticercus obtained by transmission electron microscopy. Panel (**b**) is a schematic representation of the tegument of cestodes. *Abbreviations*: bl, basal lamina; er, endoplasmatic reticulum; gg, glycogen granules; M, muscle; MI, microtriches; N, nucleus; pm, parenchymal mitochondria (anaerobic mitochondria); tm, tegumental mitochondria (aerobic mitochondria); v, vesicles.

In the case of the phylum Platyhelminthes, due to their flattened morphology, gas exchange as well as nutrient uptake can take place through the body wall because these organisms lack a circulatory system. Naturally, the uptake of O2 occurs by simple diffusion and is carried out through this structure. At this point, it is important to note that there is a gradient in the concentration of oxygen in the parasite, where the tegument, being the most exposed region, presents the highest pO2, whereas the oxygen concentration decreases when entering the internal tissues of the parasite [47]. In addition to this, there is an important relationship with the size of the parasite, as in *F. hepatica* [48].

The tegument is essential for the success of these parasites and, in fact, it plays a key role in the evolution of parasitism in these animals due to the inseparable host-parasite bond that is generated [49]. In practice, it is a barrier that protects the parasite from the host's immune system [50,51] and from the hostile conditions in the digestive tract, blood, or other organs [46]. Additionally, it serves to house the molecular systems that will serve multiple purposes such as migration through the host's body, antioxidant defense, repair of damage caused by the attack of the immune system, and evasion and modulation of the immune system response [52]. We will deal with these points at the end of this review.

#### 3.1.2. Diversity of Mitochondria

Parallel to the appearance and enrichment of O2 in the atmosphere and, consequently, the diversification of living organisms, diverse types of mitochondria were also generated, from mitoplasts to aerobic mitochondria [53,54].

Palade in 1953 [55] recognized that variation in the size, shape, and internal organization of mitochondria seems to reflect their physiological and biochemical differences in different cells of an organism. It is now well known that tissues with a high demand in their energy metabolism contain several hundred mitochondria per cell and that they have many

densely packed cristae, whereas in tissues with a lower energy demand, mitochondria with fewer cristae and smaller in size are present [56].

According to their metabolism, two large groups of mitochondria can be distinguished: aerobic and anaerobic. Aerobic mitochondria in the presence of O2 carry out the Krebs cycle and oxidative phosphorylation. In contrast, anaerobic mitochondria are structurally similar to typical mitochondria but function in the absence of O2; although their enzymatic repertoire is not very different from that of aerobic mitochondria [9,57], because many of these enzymes can catalyze the reverse reaction under certain conditions. Some enzymes of the Krebs cycle participate in these two metabolic pathways, such as fumarase and succinyl-CoA synthetase, whereas other enzymes participate in anaplerotic pathways such as phosphoenol-pyruvate kinase (PEPK) and mitochondrial malic enzyme (mME) (Figure 4). The above allows these two metabolisms, aerobic and anaerobic, to occur almost simultaneously or in different regions of a parasite, with pO2 ultimately determining their prevalence [58].

**Figure 4.** Aerobic and anaerobic energy metabolism in parasitic flatworms. Representation of the electron flow in aerobic metabolism: Panel (**a**), while Panel (**b**), represents the electron flow corresponding

to anaerobic metabolism. Abbreviations: OMM, outer mitochondria membrane; IMM, inner mitochondria membrane; Ac-CoA, Acetyl coenzyme A; ASCT, acetate succinate-CoA transferase; cyt*c*, cytochrome *c*; Fum, fumarate; FH, fumarate hydratase (fumarase); FRD, fumarate reductase; Glu-6-P, glucose 6-phosphate; Lac, lactate; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; ME, mitochondrial malic enzyme; MetMal-CoA, methylmalonyl coenzyme A; Mlt, malate; PEP, phosphoenol pyruvate; PEPCK, phosphoenol pyruvate carboxykinase; PDH, pyruvate dehydrogenase complex; PK, pyruvate kinase; Pyr, pyruvate; OAA, oxaloacetate; RQ, rhodoquinone; Succ, succinate; Succ-CoA, succinyl-coenzime A; SDH, succinate dehydrogenase; TCA, tricarboxylic acid cycle; UQ, ubiquinone.

Regarding the pO2 to which they are exposed, structurally and metabolically different mitochondria have been described in the same organism related to the gradient that is established when O2 diffuses from the tegument towards the cell parenchyma [59]; thus, it is expected that the tegument presents a higher concentration of O2 than the parenchyma [60]. In 1967, Lumsden [61] described the presence of a heterogeneous population of mitochondria in the cestode *Lacistorhynchus tenuis*, where he reports that the parenchyma cells are larger despite occurring in smaller numbers and having fewer cristae compared to mitochondria of the tegument. This differential distribution of the types of mitochondria in the tissues of the cestodes was subsequently corroborated in the *Taenia crassiceps* metacestode [62], where we determined the aerobic metabolism of the mitochondria present in the tegument of the cysticercus and were able to observe that in addition to being very numerous, they have highly developed cristae (Figure 3). The presence of aerobic mitochondria in the tegument is not exclusive to cestodes; Takamiya observed the presence of several types of mitochondria in the trematode *Paragonimus westermani* [63]. On the one hand, in the tegument, he described numerous mitochondria with a larger number of cristae and a greater amount of cytochrome *c* oxidase activity (a marker of aerobic metabolism) compared to that of the parenchyma cells, where this author reported the presence of two types of mitochondria similar in size but one being completely anaerobic and the other one only partially so.
