Mitochondrial Transplantation: Is It a Feasible Therapy to Prevent the Cardiorenal Side Effects of Cisplatin?

Abstract

Mitochondrial transplantation (MT) is a new experimental approach that has demonstrated positive results reverting mitochondrial alterations in cardiac and kidney dysfunction mainly mediated by oxidative stress. On the other hand, cisplatin is an effective and widely used antineoplastic drug in treating several cancers; however, cisplatin has notorious side effects in different organs, such as the heart, kidneys, liver, and brain; the kidney being one of the most affected. The genitourinary system is the principal excretion pathway of cisplatin, since it is removed from the blood primarily by glomerular filtration and tubular secretion, and it may cause a sudden reduction in the renal function (acute kidney injury “AKI”), in part, by inducing mitochondrial dysfunction and the consequent oxidative stress in the tubular segment. In addition, AKI may associate with cardiac alterations, as occurs in acute cardiorenal syndrome. Due to the high prevalence of renal and cardiac side effects produced by cisplatin, here we discuss the possible use of MT as a novel therapy that could protect tissues by alleviating mitochondrial dysfunction and reducing reactive oxygen species (ROS) production.

Changes in CoQ10/Lipids Ratio, Oxidative Stress, and Coenzyme Q10 during First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma (mUC)

“…Based on the current study’s results, we assume that there is an interaction between CoQ 10 and CDDP, as it has the ability to bind many hydrogens [ 13 ]. CDDP could be a Q-CYCLE proton donor leading to the stimulation of CoQ 10 production.…”

“…Therefore, the accumulation of CDDP in the cell leads to the damage of nuclear DNA (nDNA), mtDNA, and also to the electron transport system. CDDP leads to the activation of NADPH, a reduction in antioxidants, and an enhancement in reactive oxygen species (ROS) [ 13 ]. ROS, composed of free radical and non-free radical oxygen intermediates—hydroxyl radical, hydrogen peroxide, singlet oxygen, and superoxide—are of great importance in homeostasis and cell signaling.…”

Oxidative Damage as a Fundament of Systemic Toxicities Induced by Cisplatin—The Crucial Limitation or Potential Therapeutic Target?

“…Amador-Martínez et al [40] explained in detail how the process of mitochondrial dysfunction affects kidney cells and leads to acute kidney injury and, eventually, renal cell apoptosis. After entrance into the cells, cisplatin accumulation in the mitochondria occurs due to the exceptional reactivity of cisplatin with proteins and mitochondrial DNA (mtDNA), while the amount of cisplatin that reacts with nuclear DNA (nDNA) is minimal.…”

“…The processes underlying cisplatin-induced mitochondrial dysfunction and, thus, acute renal toxicity are closely related to a higher stability of cisplatin-mtDNA reaction products, increasing the concentration of superoxide radical in mitochondria that cannot exit, and mtDNA in comparison to nDNA have a higher mutation rate, which then leads to the development of oxidative stress, inflammation, and apoptosis. High ROS levels induce both structural and functional discrepancies in mitochondria, ultimately causing severe renal tissue injuries [40].…”

“…Cisplatin can interact and activate a number of signaling pathways, like MAPK, caspase-3, Bcl-2, p53, and p21, and affect the mitophagy and mitochondrial dynamics, thus causing kidney cell damage [40]. These and many other inflammatory responses can be triggered by cisplatin-induced tissue damage.…”