Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration

Abstract

Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates. Autophagy flux assays confirmed that the Dox-induced accumulation of autophagosomes occurs due to blockage of the lysosomal degradation process. Dox-induced autophagosomes and autolysosome accumulation were confirmed in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. Mitochondria isolated from acute Dox-treated hearts showed significant suppression of oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity also exhibited time-dependent accumulation of LC3B II levels and increased accumulation of green puncta in GFP-LC3 Tg hearts. Mitochondria isolated from chronic Dox-treated hearts also showed significant suppression of mitochondrial OCR. The in vivo impairment of autophagic degradation process and mitochondrial dysfunction data were confirmed in vitro using cultured neonatal cardiomyocytes. Both acute and chronic Dox-associated cardiomyopathy involves a multifocal disease process resulting from autophagosomes and autolysosomes accumulation, altered expression of mitochondrial dynamics and oxidative phosphorylation regulatory proteins, and mitochondrial respiratory dysfunction.

Involvement of Yes‐associated protein 1 (YAP1) in doxorubicin‐induced cytotoxicity in H9c2 cardiac cells

“…Cardiomyocyte‐specific deletion of topoisomerase IIβ gene protects mice from the development of doxorubicin‐induced progressive heart failure, decreasing cardiotoxicity (Zhan et al, ). Furthermore, multiple mechanisms, such as autophagy dysregulation and mitochondrial dysfunction, are implicated in doxorubicin‐induced cardiotoxicity (Abdullah et al, ). Most of these cellular events result in an increase in cardiac cell death.…”

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

“…Previous analysis showed little changes in Drp1 and more mitochondrial elongation in doxorubicin-treated hearts (Abdullah et al, 2019). It was also suggested that levels of Drp1 and Drp1 Ser 616 phosphorylation were increased following doxorubicin challenge (Xia et al, 2017;Catanzaro et al, 2019).…”

“…Clearance of damaged mitochondria exerts a critical role in the mitochondrial quality control. There is emerging evidence for defective mitochondrial autophagy or mitophagy in mitochondrial damage from doxorubicin-induced cardiotoxicity (Abdullah et al, 2019). Mitochondrial autophagy is a conserved cellular process to degrade and recycle damaged mitochondria through formation of autophagosomes and fusion with lysosomes.…”

Mechanisms of Anthracycline-Induced Cardiotoxicity: Is Mitochondrial Dysfunction the Answer?

“…Unfortunately, ANTs are known to disrupt the major degradative/recycling process of mitochondria, namely autophagy (46,47). Several studies found that acute administration of high-dose ANTs can induce the accumulation of both LC3 and p62, the major autophagy markers, with a reduction in ATP levels in mouse hearts, and a significant suppression of oxygen consumption rate (OCR) in their mitochondria (46). Further analysis from Li et al demonstrated that DOX blocks cardiomyocytes autophagic flux mediating a strong accumulation of undegraded autolysosomes.…”