**2. Why we choose mitochondria for drug targeting**

The mitochondrion is as a respiratory organelle exists in almost all eukaryotic nucleated cells. Its unique structure is consisted of four distinct sub-structures with different specific functions: the mitochondrial matrix, the inner mitochondrial membrane (IMM), the outer mitochondrial membrane (OMM) and the intermembrane space (IMS). The structure of the inner mitochon‐ drial membrane (IMM), is extensively folded and compartmentalized. The numerous invagi‐ nations of the membrane are called cristae, which house the 4 complexes of the mitochondrial respiratory chain and ATP synthase, controlling the vital levels of cellular bioenergetics. This primary function of the mitochondrion is responsible for supplying cellular energy, the reason why we call it power plant of the cell.'' However, it is not the only important function of mitochondria in the cell [6]. Adenosine triphosphate (ATP) production through the oxidative phosphorylation (OXPHOS) process requires a continuous flow of electrons. As such, mito‐ chondria are the major so are the major source of reactive oxygen species (ROS, i.e. superoxide and H2O2), generated as byproducts of the ETC. ROS reflect the level of cellular oxidative stress, causing severe damage to macromolecules when overproduced. Consequently, according to the Harman's oxidative stress theory, they have been linked to aging, age-related pathologies, and death. However, when produced in a controlled amount, ROS may also play important signaling roles in various redox-dependent processes, including apoptosis, cell proliferation and hypoxia. Furthermore, mitochondria are active players in cellular calcium homeostasis. Mitochondrial Ca2+ accumulation regulates functions as diverse as aerobic metabolism and induction of cell death. Finally, mutations in mitochondrial DNA (mtDNA) are responsible for many mitochondrial metabolic disorders, and are thought to contribute to aging by promoting apoptosis. Thus, because of their pivotal role in regulating cell life and death, mitochondria represent an attractive target for mitochondrial gene therapy as well as drugs treating either degenerative or hyper proliferative diseases (figure 1) [7].

Some aspects of mitochondrial biogenesis and some important roles of mitochondria in cell function are illustrated. One major function of mitochondria is the production of energy (ATP) via aerobic metabolism of glucose which is called oxidative phosphorylation. Initially, glucose is metabolized to pyruvate through cytosolic glycolysis (anaerobic metabolism). Voltage-dependent anion channels (VDACs), also called porin channels, allow low molecular weight molecules to enter the mitochondrial inter membrane space. Following the activation of AMPK (AMP-dependent kin‐ ase), cell responds to the decreased ATP/ADP ratio in the cytosol through alterations in AMP, and affects several tar‐ gets. Mitochondrial mtDNA encodes 37 genes that are involved in the synthesis of the respiratory chain and the ATP production. Additional proteins are imported through TIM (transporter inner membrane) and TOM (transporter outer membrane), translocases of the inner and outer membranes that transport nuclear-encoded proteins into mitochondria. The adenine nucleotide translocase (ANT) enables the mitochondrion to import ADP and export ATP. Mitochondria also contribute to calcium homeostasis by taking up calcium into the mitochondrial matrix through the calcium uni‐ porter in response to changes in cytosolic calcium. In addition, mitochondria play a crucial role in cell death such as apoptosis and necrosis. When apoptotic signals occur, the outer membrane becomes compromised and the mitochond‐ rion experiences mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c (cyt c) and many other pro-apoptotic proteins from the intermembrane space into the cytosol where they activate apoptotic cell death [6].

**Figure 1.** Mitochondrial biogenesis and function.

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

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

The mitochondrion is as a respiratory organelle exists in almost all eukaryotic nucleated cells. Its unique structure is consisted of four distinct sub-structures with different specific functions: the mitochondrial matrix, the inner mitochondrial membrane (IMM), the outer mitochondrial membrane (OMM) and the intermembrane space (IMS). The structure of the inner mitochon‐ drial membrane (IMM), is extensively folded and compartmentalized. The numerous invagi‐ nations of the membrane are called cristae, which house the 4 complexes of the mitochondrial respiratory chain and ATP synthase, controlling the vital levels of cellular bioenergetics. This primary function of the mitochondrion is responsible for supplying cellular energy, the reason why we call it power plant of the cell.'' However, it is not the only important function of mitochondria in the cell [6]. Adenosine triphosphate (ATP) production through the oxidative phosphorylation (OXPHOS) process requires a continuous flow of electrons. As such, mito‐ chondria are the major so are the major source of reactive oxygen species (ROS, i.e. superoxide and H2O2), generated as byproducts of the ETC. ROS reflect the level of cellular oxidative stress, causing severe damage to macromolecules when overproduced. Consequently, according to the Harman's oxidative stress theory, they have been linked to aging, age-related pathologies, and death. However, when produced in a controlled amount, ROS may also play important signaling roles in various redox-dependent processes, including apoptosis, cell proliferation and hypoxia. Furthermore, mitochondria are active players in cellular calcium homeostasis. Mitochondrial Ca2+ accumulation regulates functions as diverse as aerobic metabolism and induction of cell death. Finally, mutations in mitochondrial DNA (mtDNA) are responsible

most therapeutic benefit [4].

62 Toxicology Studies - Cells, Drugs and Environment

drugs acting on targets in the mitochondrion [5].

**2. Why we choose mitochondria for drug targeting**
