Kiyoshi Kita

By Kenji Hikosaka, Keisuke Komatsuya, Shigeo Suzuki and Kiyoshi Kita

Mitochondria are organelle, which is found in most eukaryotic cells, and play an important roll in production of many biosynthetic intermediates as well as energy transduction. 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 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.

Part of the book: An Overview of Tropical Diseases

By Shigehiro Enkai, Kimitoshi Sakamoto, Miho Kaneko, Hirokazu Kouguchi, Takao Irie, Kinpei Yagi, Yuka Ishida, Jun Matsumoto, Yuzaburo Oku, Ken Katakura, Osamu Fujita, Tomoyoshi Nozaki and Kiyoshi Kita

As an efficient drug for alveolar echinococcosis (AE) is still not available, new chemotherapy targets are necessary. The mitochondrial respiratory chain may be a good drug candidate because parasite respiratory chains are quite different from those of mammalian hosts. For example, Ascaris suum possesses an NADH‐fumarate reductase system (fumarate respiration) that is highly adapted to anaerobic environments such as the small intestine. It is composed of mitochondrial complex I (NADH‐ubiquinone reductase), complex II (succinate‐ubiquinone reductase), and rhodoquinone. We previously demonstrated that fumarate respiration is also essential in E. multilocularis. Quinazoline, a complex I inhibitor, inhibited growth of E. multilocularis larvae in vitro. These results indicate that fumarate respiration could be a target for E. multilocularis therapy. In the current chapter, we focused on complex II, which is another component of this system, because quinazoline exhibited strong toxicity to mammalian mitochondria. We evaluated the molecular and biochemical characterization of E. multilocularis complex II as a potential drug target. In addition, we found that ascofuranone, a trypanosome cyanide‐insensitive alternative oxidase inhibitor, inhibited E. multilocularis complex II at the nanomolar order. Our findings demonstrate the potential development of targeted therapy against Echinococcus complex II.

Part of the book: Echinococcosis

By Madhavi P. Paranagama and Kiyoshi Kita

Human mitochondrial complex II is an intriguing enzyme, which has been the focus of medical research during the past few decades since it contributes to pathogenesis of mitochondrial diseases as well as a target for chemotherapy. Reactive oxygen species (ROS) produced by this enzyme has been implicated in both these conditions. While ROS produced from mutated mitochondrial complex II has been implicated in pathogenesis of mitochondrial diseases, ROS produced from pharmacologically inhibited mitochondrial complex II has been implicated in cancer cell death. In this chapter, we show that inhibition of mitochondrial complex II in human cancer cells with atpenin A5 produces detectable levels of ROS while normal cells do not. Thus, this enzyme may be used as a potential target for developing new anticancer drugs to trigger ROS-mediated selective death of cancer cells.

Part of the book: Mitochondrial Diseases