Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Abstract

Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.

Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

“…Chemotherapy drugs also contribute to cardiomyocyte dysfunction and death by affecting mitochondrial function. For example, doxorubicin-induced upregulation of p53 inhibits protective mechanisms in cardiac fibroblast mitochondria [ 20 ], and administration of mitochondria-associated protein LRPPRC protects against doxorubicin-induced cardiac injury by inhibiting ROS production [ 60 ]. Anthracycline-mediated cardiotoxicity is also associated with dysregulation of mitochondrial metabolism, although the detailed molecular mechanisms involved are not fully understood [ 23 ].…”

“…Previous studies have reported that targeted cancer therapies, such as doxorubicin [ 15 ], anthracycline [ 16 ], and cantharidin [ 17 ], can result in cardiovascular toxicities. The adverse effects of chemotherapy drugs may result from impaired mitochondrial function, increased oxidative stress [ 15 , 18 ], increased mitochondria-proteasome interactions [ 19 ], impaired mitochondrial autophagy [ 20 , 21 ], activation of mitochondrial inflammation signaling pathways such as NF- κ B [ 22 ], mitochondrial energy metabolic dysfunction [ 23 ], and mitochondrial apoptosis [ 24 ]. In addition, ER-mediated abnormalities in intracellular calcium signaling, protein misfolding as a result of ER stress, and ER-dependent cell apoptosis [ 25 – 27 ] can also contribute to cardiomyocyte damage during chemotherapy.…”

Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy

“…However, the role of PINK1/Parkin-mediated mitophagy in DOX-induced cardiomyopathy is still in dispute. Some studies claimed that enhanced mitophagy could protect against DOX cardiotoxicity (Mancilla et al, 2020;Xiao et al, 2020), while others stood on the opposite (Gharanei et al, 2013;Catanzaro et al, 2019). These mixed results might be explained by the different model used, different DOX concentrations, different time of treatment, and different degree of cell damage.…”

Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy

“…DOX can also dysregulate the cytosolic and mitochondrial signaling axes, which leads to mitophagy destruction and arrhythmias, causing impaired mitochondrial clearance, the accumulation of dysfunctional mitochondria, ROS overload, and a lack of Adenosine triphosphate (ATP). Meanwhile, DOX can also phosphorylate BNIP3 and then inhibit mitophagy, which is closely related to the mitochondrial sirtuins (SIRT3-SIRT4) pathway ( 26 , 27 , 150 , 206 , 207 , 221 , 225 , 227 , 228 ). Recently, it was reported that excessive DOX can also significantly induce elevated insulin-like growth factor-II receptor (IGF-IIR) expression, IGF-IIR induces myocardial hypertrophy and cardiomyocyte death in a paracrine/autocrine manner.…”

“…Moreover, the decrease of mitophagy can lead to excessive ROS in cardiac cells, further promote the release of cytochrome c and cysteine aspartate protease, disrupt the stability of mitochondria DNA, inhibit the activity of respiratory electron-transport chain, and reduce both oxygen utilization and consumption. It can even initiate mitochondrial apoptosis and induce mitochondrial damage (26, 88, [219][220][221][222][223][224]. Parkin overexpression increases mitophagy, which aggravates cell death through poisoning.…”