**Mitochondrial Targeting for Drug Development**

Jalal Pourahmad, Ahmad Salimi and Enayatollah Seydi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/59719

#### **1. Introduction**

What is the reason that mitochondrion is so attractive target for pharmacotherapy? The problem raised is a bit complex. Although the appearance of mitochondria in animal cells started more than one million years ago, when the proteobacteria (in particular, Rickettsiales or close relatives) entered and practiced coexistence inside eukaryotic cells via endocymbiosis, But the biological science started to pay attention on mitochondria in the middle of 19th century, the time that mitochondria were discovered in tissue section of liver and flight muscle. The earliest definition of this organelle in cells was written by Richard Altmann on 1890, when he named them as ''bioblasts'' and hypothesized that they were ''elementary organisms'' living inside cells with ''vital functions'' [1]. After 1890, the progress in understanding the structure and function of mitochondria was quite steady, but we can single out major milestones in every decade. In the 1950s, investigators analyzed mitochondria by electron microscopy and characterized that they are the sites of respiration, Oxidative Phosphorylation (OXPHOS) and fatty acid oxidation. In the 1960s, investigators found out mitochondrial DNA (mtDNA) and described chemiosmotic theory. In the 1980s, the first consummate sequence of mammalian mtDNA and the first molecular identification of a cause of mitochondrial diseases were reported. A great incrementation in interest on mitochondria occurred in 1996, when research‐ ers demonstrated that the organelles are associated with programming cell death or apoptosis [2]. After this manifestation, mitochondrial study commenced growing as a biomedical field. Owing to the unique structure and function of mitochondria, several clinically used drugs can improve or damage their bioenergetics. These drugs can act via the regulation of: (a) perme‐ ability transition pores (PTPs), (b) fatty acid uptake or oxidation, (c) the electron transport chain (ETC), (d) cardiolipin (CL) content (e) ion channels and transporters, (f) Adenosine triphosphate (ase) (ATPase) and (g) mtDNA and protein synthesis [3]. Mitochondria are subcellular organelles that play pivotal roles essential for energy (ATP) production, metabolism,

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and homeostasis. In addition, mitochondria orchestrate some survival and cell death signaling. The reason why the mitochondria is considered as a potential drug target for the treatment of hyperproliferative and metabolic disorders. Unsimilarities in the reduction/oxidation condi‐ tion of tumor versus non-tumor cells may be beneficial to get selective cytotoxic and anticolonygenic effect on tumor cell populations. It was shown that pro-oxidant drugs, including Elesclomol and Trisenox have therapeutic benefits in the treatment of cancer. Findings obtained with Bz-423 in mouse demonstrate the potential for mitochondria-targeted drugs to control disorders of immune function. Investigation associating an elevated oxidant state with mitochondrial damage, aging dictates, and degenerative disease the need for a better under‐ standing of how and when pharmacological manipulation of mitochondrial function prepares most therapeutic benefit [4].

Mitochondria carry out vital biochemical functions essential for cells such as homeostasis calcium, cell death and survival, in addition to ATP production. They represent a convergence point for death signals triggered by both intracellular and extracellular cues. Not surprisingly it's incoherent, therefore, mitochondria additionally offer targets for xenobiotics to exert either detrimental or therapeutic effects on cell survival and function. Efforts to harness mitochon‐ drial targets for therapeutic benefit have focused largely on cancer, although treatments for ischemia, metabolic diseases and neurodegenerative diseases also are being explored. This chapter will describe current thinking and recent advances in the discovery of small molecule drugs acting on targets in the mitochondrion [5].
