Abstract
Introduction: Doxorubicin (Dox) associated cardiotoxicity limits its use in clinical practice. Despite extensive studies it is still unclear if Dox-induces autophagy activation or inhibition. Also a role for autophagy dysregulation contributing to mitochondrial dysfunction in Dox-cardiotoxicity is unknown. Hypothesis: Dox-mediated impairment of the autophagy degradation process contributes to mitochondrial dysfunction during the development of cardiomyopathy. Methods and results: Time course study of acute Dox treatment (20mg/kg, i.p.) showed accumulation of LC3-II in heart lysates at day five. We also confirmed Dox-induced autophagosome accumulation in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. The autophagy flux assay confirmed that Dox-induced accumulation of autophagosome is due to blockade of the lysosomal degradation process. Mitochondria isolated from acute Dox-treated hearts (at day 5) showed significant suppression of the oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity induced by four weekly consecutive i.p. Injections of Dox (5 mg/kg each) also exhibited time-dependent accumulation of LC3 puncta in GFP-LC3 Tg hearts. LC3-II levels in both whole cell and mitochondrial fraction were increased in Dox-treated hearts. The mitochondria in chronic dox-treated hearts (12 weeks) also showed significant suppression of OCR. To test whether autophagy induction/activation can rescue mitochondrial dysfunction in Dox-cardiotoxicity, we subjected cardiac specific αMHC-Atg7 Tg mice to acute Dox treatment. Mitochondria from Dox-treated αMHC-Atg7 Tg mice (at day 5) exhibited significant preservation of mitochondrial respiratory parameters including basal, ATP linked and maximal respiration. Conclusions: Our study confirmed that both acute and chronic Dox-cardiotoxicity is associated with inhibition of the autophagic degradation process associated with suppression of mitochondrial respiration. Notably, autophagy activation/induction preserves mitochondrial function in Dox-treated hearts, underscoring the importance of autophagy in maintaining physiologically normal mitochondrial respiration in hearts under genotoxic stress.
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