**6.1. The acute mitochondrial toxic effect of doxorubicin**

The acute toxic effect of DOX on mitochondria has been reported to rely on its dose, especially redox cycling and ETC blocking. A low concentration of DOX treatment has been reported to have minimal alternation to ATP production and MMP, resulting from enhancing hydroxyl radical (\*OH), H2 O2 , and oxygen consumption. Although up to 160 μM DOX concentration has been emphasized, redox cycling is the primary process to augment ROS production; ETC blocking is the primary source of ROS manufacture at densities higher than 160 μM. Until it reaches a threshold, which means 480 μM, mitochondrial toxicity is progressively enhanced. Eventually, mitochondrial collapse is inevitable, resulting in MMP dissipation, improvement in ROS production, inhibition of ATP production, and also oxygen utilization. A dose of 1 mg/kg of DOX has been reported to increase superoxide radicals within 2 h, although a 37 mg/m2 dose, which equals to 5–30 μM mitochondrial concentration, has the same effect on human beings [44].

fission (divide) and fusion. Fission could cause mitophagy, apoptosis, and cell proliferation. However, fusion provides a homogeneous network of mitochondria. Imbalance of the mitochondrial dynamic causes it to lose cell function, e.g., when the shift towards fission could initiate apoptotic cell death due to severe ROS production. In contrast, the change towards fusion would increase mitochondrial dysfunction because of extinguishment of the mitophagy mechanism. The dynamic provides healthy, functional mitochondria and cells [39].

Mitochondrial Dysfunction Associated with Doxorubicin http://dx.doi.org/10.5772/intechopen.80284 343

To maintain its function the heart prefers to metabolize fatty acid in mitochondria and peroxisomes via β-oxidation due to its high demand energy [14]. Mitochondrion starts energy production by the tricarboxylic acid cycle (TCA) in the ETS. Mitochondrial ATP is synthesized by ETS steps. Although TCA elements are placed in the mitochondrial matrix, except for succinate dehydrogenase, ETS elements having a spherical shape are present at the mitochondrial inner membrane and project to the mitochondrial matrix. The space between the inner and outer layer is called the intermembrane space or mitochondrial cytosol. A molecule with hydrophilic structure can transit the inner membrane as a requirement of the transport system. The outer membrane of mitochondria can pass through almost all particles less than 10,000 Da [10]. The respiratory chain is under the control of four complexes: complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome-*c* reductase), and complex IV(cytochrome-*c* oxidase) [34] (**Figure 5**). Complex V is ATP synthase [11]. After synthesis, ATP can be transferred from the inner mitochondrial membrane to the cytosol through ANT and the outer membrane VDAC. MPT induction opens the nonselective pores permitting the diffusion of a 1.5 kDa small molecule [14]. Electrons can be relocated from complex I (NADH dehydrogenase) and II (succinate dehydrogenase) to coenzyme Q10 with a quinine structure as DOX. Then, particles are moved to complex III, cytochrome-*c*, and complex IV. Eventually, oxygen can capture the particle, resulting in water synthesis (**Figure 5**). All ETS elements associated with the enzyme are placed near the matrix surface of the inner mitochondrial membranes. It has been reported that complex I and II could not reach the particles in the mitochondrial cytosol from any organ and any cancer cells, except the heart. The mitochondria of cardiac tissue has two position on the outer surface of inner mitochondrial membrane and faces the matrix [10]. However, overexposed DOX causes mitochondrial dysfunction, consisting of decreasing state 3 respiration, complex I, and ANT activities. Moreover, lengthy DOX treatment increases susceptibility to calcium, resulting in

Bioenergetics failure may be primarily a mechanism of DOX cardiotoxicity [13]. So, the other molecular base of DOX toxicity on noncancerous tissue relies on the destruction of mtDNA. Oxidative stress leads to damage to mtDNA, especially heart tissue. Additionally, DOX represents the harmful effect of mtDNA much more than nuclear DNA. If the integrated knowledge that the mtDNA repair system is fragile vs. the nuclear DNA system, DOX is understood to be highly toxic to mitochondria [10]. The mitochondrial genome has 13 subunits of ETC codes, which are almost all of the ETC complex, except complex II, a succinate dehydrogenase encoded by nuclear DNA [13]. mtDNA has also been encoded by mitochondrial ribosomal and transfer RNA [10]. DOX damages mtDNA via elevation of ROS [13]. Oxidative damage of DNA has been evaluated by using 8-OHdG formation. After DOX treatment, 8-OHdG has been reported to reach a peak value at 24 h, but a baseline value at 14 days [13]. The chronic

dissipation of MMP at low and high concentrations [13].
