**Mitochondria of Malaria Parasites as a Drug Target**

Kenji Hikosaka, Keisuke Komatsuya, Shigeo Suzuki and Kiyoshi Kita

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61283

#### **Abstract**

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Mitochondria are organelle, which is found in most eukaryotic cells, and play an im‐ portant roll in production of many biosynthetic intermediates as well as energy trans‐ duction. Recently, it has been reported that mitochondria contribute to cellular stress responses such as apoptosis and autophagy. These functions of mitochondria are known to be essential for survival and maintenance of homeostasis. The mitochondria of malaria parasites are quite different from those of their vertebrate hosts. Because these differences markedly contribute to drug selectivity, we have focused on the *Plas‐ modium* mitochondrion to develop antimalarial drugs. Here we summarize recent ad‐ vances in our knowledge of the mitochondria of malaria parasites and discuss future prospective antimalarial drugs targeting the parasite mitochondrion.

**Keywords:** malaria, *Plasmodium*, mitochondria, antimalarial drugs, atovaquone, 5 aminolevulinic acid

### **1. Introduction**

Malaria is a major global health problem, shortening over 500,000 human lives annually, mainly children in tropical and subtropical regions [1]. Due to difficulties in developing antimalarial vaccine, chemotherapy is important for controlling malaria. Parasites causing malaria, however, can rapidly develop resistance against the available chemotherapies [2]. Thus, new drugs with different modes of action are urgently needed. Malaria parasites are disseminated by female *Anopheles* mosquitoes and belong to the *Plasmodium* genus. *Plasmodi‐ um* has a complicated life cycle, comprising two major cycles: asexual multiplication in humans and sexual multiplication in mosquitoes (Figure 1) [3]. The parasites invade the hepatocytes of their host and mature into merozoites. After release, the merozoites infect red blood cells (RBCs). In the RBCs, the parasites differentiate into the following stages: ring, trophozoite, and schizont. Subsequently, the infected RBCs burst and release merozoites, which invade

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uninfected RBCs. These stages are called the erythrocytic stages, where the parasites multiply asexually. Following the establishment of infection, some parasites differentiate to gameto‐ cytes [4]. The gametocyte stage is essential for subsequent transmission because this is the only stage where the organism undergoes sexual development in the mosquito vector. Therefore, *Plasmodium* has a complex life cycle, which seems to be an adaptation to its host environment [5]. In addition to the complex life cycle, the malaria parasites have evolved sophisticated pathways of energy transduction to adapt to their hosts.

**Figure 1.** Life cycle of the human malaria parasite *Plasmodium falciparum.*

Mitochondria, an organelle arising from alpha-proteobacterium engulfed by a eukaryotic progenitor [6], play a key role in energy transduction of eukaryotic cells. In vertebrates, that can become a host for malaria parasites, mitochondria have been reported to contribute to cellular responses such as autophagy, apoptosis, and ATP production [7]. The vertebrate mitochondrion comprises two separate and functionally distinct outer and inner membranes that form cristae, and it also contains its own circular genome, the mitochondrial genome (mtDNA). With few exceptions, vertebrate mtDNA is approximately 16 kb in size, encoding 37 genes: two for ribosomal RNAs (rRNAs), 13 for proteins, and 22 for tRNAs [8]. In contrast to the vertebrate mitochondrion, the *Plasmodium* mitochondrion is a single tubular organelle structure [9] that possesses a 6-kb mtDNA, encoding only three genes for proteins and highly fragmented rRNA genes [10], and it is the smallest eukaryotic mtDNA. Furthermore, the erythrocytic stages of the parasite have been considered to mainly rely on glycolysis, with secretion of end products such as lactate and pyruvate [11, 12]. The mitochondria of malaria parasites are thus quite different from those of their vertebrate hosts. Because these differences markedly contribute to drug selectivity, we have focused on the *Plasmodium* mitochondrion to develop antimalarial drugs. Here we summarize recent advances in our knowledge of the mitochondria of malaria parasites and discuss future prospective antimalarial drugs targeting the parasite mitochondrion.
