**7. Conclusion**

and skin. Cardiac cCK has two forms as a homodimer (MMCK and/or BBCK) or heterodimer (MBCK), which is a cardiac-specific form [24]. According to this knowledge, it is said that MBCK can usually be determined as an indicator of a heart attack. sMtCK is the mainly octameric form [24] and places the outer intermembrane space and mitochondrial cristae between membranal protein ANT in the inner membrane and VDAC in the outer layer [24]). MtCK has high affinity to cardiolipin [14] and the outer surface of the inner mitochondrial membrane [24]. It must not be forgotten that DOX has a great relationship with cardiolipin. So, one of DOX's targets is MtCK. Moreover, DOX oxidizes MtCK at cysteine residues. Besides oxidation, DOX leads to inactivation of MtCK, resulting in enhanced embryonic CK isoform

MtCK can efficiently produce PCr from creatine [24, 43]. Transformation of creatine to PCr firmly binds between energy generation and utilization. MtCK, an octameric, accompanies ANT, and VDAC (porin) [43]. ANT can transfer ADP to matrix space. Then, ADP resynthesizes ATP through oxidative phosphorylation. However, PCr can be sent to the cytosol via VDAC [24]. PCr is utilized by cCK to maintain the subcellular local ATP/ADP ratio [24].

Although DOX inactivates all CK, MtCK is especially destroyed [43] by the drug through dissociation of its structure from octamer to dimer [24, 43] or infusion of binding MtCK at mitochondrial membranes, such as cardiolipin [24]. Moreover, cardiac MtCK has been reported to be more sensitive to DOX than uMtCK, leading to selective toxicity in heart tissue. The inactivation of MtCK by DOX is linked to the drug's dosage. At a low dose below 100 μM, MtCK's inactivation occurs because of DOX's redox modification from its cysteine residues. Its high treatment, however, depresses MtCK due to ROS production. Furthermore, DOX and MtCK have been indicated to have a standard feature, they tend to attach an inner mitochondrial membrane, providing high DOX concentration around the MtCK. Additionally, when DOX

to oxidative and nitrous stress, which means that CK is very vulnerable to the redox status of cells. Even a 2 μM DOX concentration has been reported to lead to dimerization of MtCK (ordinarily octameric), and augment the inhibition and dimerization at a 20 μM intensity. Also, it is indicated that total CK activity has been noticed to reduce (by nearly 20%) for DOX treatment concentrated at 20 μM. Under this circumstance, CK has still been maintaining its function due to a compensatory mechanism, which reduces MCK (a myofibrillar isoform) and high BCK (a fetal isoform) that is elevated by heart failure or cardiac hypertrophy. It is vital to know that CK shift is reported to be within 1 h at 2 μM of DOX. So, CK system dysfunction might probably participate in DOX-mediated heart failure. MtCK inhibition by dimerization not only causes energy transfer from mitochondria to the cytosol but also influences the mitochondrial respiratory chain. Moreover, this inhibition destroys the three-modal interaction between MtCK, ANT, and VDAC, which means that MtCK plays a role in MPT. So, damage to the modal interaction could first trigger apoptosis. Besides programmed cell death, myofibrillar CK functionally integrates with SERCA. When a CK defect occurs, cytosolic Ca2+ balance is destroyed, leading to defects in contraction and relaxation coupling due to Ca2+ accumulation. Ca2+accumulation could also trigger apoptosis. This is why dysfunction of CK causes innate

, CK inhibition via DOX accelerates. The inhibition is linked

expression [14].

352 Mitochondrial Diseases

is activated by peroxidase/H2

apoptosis in two ways [43].

O2

It is impossible to ignore DOX therapy from cancer patients' treatment due to its inevitable chemotherapeutic efficiency on a variety of cancers. Unfortunately, there is limited knowledge available on DOX's cardiotoxicity, particularly mitochondriopathy. This is why the molecular clarifying mechanism of DOX's myocardial and mitochondrial toxicities will hopefully overcome the side effects and increase the survival rate of cancer patients as well. Therefore, further studies are needed to evaluate the detrimental effects of DOX on mitochondria to restore its limited utilization in cancer patients' therapy.
