Preface [Hot topic: Mitochondria as a Target of Medicinal Chemistry (Guest Editor: Dongchon Kang)]

Mitochondria are responsible for over 80% of ATP production in normal cells. Without mitochondrial ATP production, individuals could not maintain their normal functions or survive [1]. Although mitochondria have long been considered solely to be a powerhouse for production of cellular energy, recently mitochondria have been clearly recognized to play a central role in execution of apoptosis or programmed cell death; many mitochondrially localizing proteins have been identified as pro- or anti-apoptotic factors. Thus, mitochondria are a kind of an arsenal. In addition, mitochondria are involved in cell proliferation and differentiation [2]. Mitochondria may also be an operating tower. Thus mitochondria regulate three essential parts of life: living, dying, and growing. Considering all these critical features of mitochondria, it is natural that mitochondria can be a very effective target of medicinal drugs. In this special issue, we focus on mitochondria from therapeutic aspects. For better understanding, Ohta overviewed the mitochondrial diseases with mitochondrial DNA mutations and the apoptotic signaltransduction pathways with special reference with mitochondria [3]. Mitochondria account for ∼90% of cellular O2 consumption due to ATP production by oxidative phosphorylation, i.e. the aerobic ATP production. The O2 consumption for the aerobic ATP production inevitably accompanies production of reactive oxygen species (ROS). It is considered that 1∼5% of the O2 consumed is converted to ROS. This huge amount of the ROS production by mitochondria is involved in a variety of pathological conditions and furthermore contributes to the cumulative oxidative damages of organs and tissues with age. The proper control of the mitochondrial ROS is crucial for coping with many pathological situations and maintaining physiological states. Inoue et al. described critical importance of the mitochondrial ROS management [4]. Mitochondrial dysfunction in neurodegeneration, e.g. Parkinson disease and Alzheimer disease, is one of keen interests in aging processes. 1-Methyl-4-phenylpyridinium ion (MPP+) causes Parkinson disease-like symptoms in human. This drug accumulates selectively in mitochondria of dopaminergic cells and impairs mitochondrial functions directly and indirectly, giving many insights into the mitochondrial roles in neurodegenrative diseases and neuronal aging per se. Kotake and Ohta extensively delineated the mechanisms of the drug-induced cell damage using derivatives of MPP+ [5]. Induction of apoptosis in damaged cells is an essential part of a physiological cancer prevention system. Artificial or forced induction of apoptosis in cancer cells, in turn, becomes a valuable anti-cancer therapy. Mitochondria occupy a central position of apoptotic pathways. Morisaki and Katano proposed theoretically and experimentally that mitochondria-targeting drugs are useful alternatives as anti-cancer drugs [6]. Mitochondria harbor their own genome. This mitochondrial genome is indispensable for the normal construction of the respiratory chain responsible for the aerobic ATP production. The mitochondrial genome is more fragile than nuclear genome in part due to its location in the ROS-producing organelle [7]. Patients with mutations of the mitochondrial genome mainly suffer from encephalomyopathy partly because both of brain and muscle are highly energy-demanding organs. Currently we do not have effective and practical therapies for those patients. Schon and DiMauro reported their unique therapeutic approaches to increase the ATP production by using medicinal drugs or by introduction of mitochondrial genes into nuclear genome [8]. ATP is essential not only for human individuals but also for parasites living on the hosts. Therefore if we take advantage of the differential properties of the respiratory chain between hosts and parasites, the mitochondrial machineries of parasites can be selectively attacked. Kita et al. beautifully demonstrated this example [9]. All articles in this special issue unambiguously illustrate a variety of aspects of mitochondria as a therapeutic target. I believe that these articles help us understand mitochondria from a point of view of medicinal chemistry. References [1] Kang, D.; Takeshige, K.; Sekiguchi, M.; Singh, K. K. (1998) in Mitochondrial DNA Mutations in Aging, Disease and Cancer (Singh, K. K., ed), pp. 1, Springer-Verlag and R.G. Landes Company, Austin. [2] Rochard, P.; Rodier, A.; Casas, F.; Cassar-Malek, I.; Marchal-Victorion, S.; Daury, L.; Wrutniak, C.; Cabello, G. J. Biol. Chem. 2000 275, 2733. [3] Ohta, S. this issue. [4] Inoue, M.; Sato, E.; Nishikawa, M.; Park, A.-M.; Kira, K.; Imada, I.; Utsumi, K. this issue. [5] Kotake, Y.; Ohta, S. this issue. [6] Morisaki, T; Katano, M. this issue. [7] Kang, D.; Hamasaki, N. Curr. Genet. 2002 41, 311. [8] Schon, E.; DiMauro, S. this issue. [9] Kita, K.; Nihei, C; Tomitsuka, E. this issue.