title: Autophagic dysregulation in doxorubicin cardiomyopathy.
abstract: Doxorubicin (DOX)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades; however, molecular mechanisms underlying DOX cardiotoxicity are still being uncovered. Although the majority of prior research have implicated nuclear and mitochondrial events to be an important etiological aspects of DOX cardiomyopathy, recent discoveries in autophagy have highlighted the renewed interest in the role of lysosome in DOX cardiomyopathy. Indeed, dysregulation of lysosomal autophagy is observed in pre-clinical models of DOX cardiotoxicity. In this review, we provide a comprehensive overview on mechanisms describing regulation of the autophagy pathway by DOX and its influence on cardiotoxic outcomes. We have put specific emphasis on experimental models, dosing and treatment duration with DOX, and methods to monitor autophagy, all of which contribute to inconsistencies observed in the literature. We have clarified processes by which DOX dysregulates macroautophagy in the heart by primarily focusing on the contribution of LC3, p62, Beclin, mTOR and AMPK pathways. We have also highlighted the impact of DOX on mitochondrial reactive oxygen species (ROS) and its contribution to the process of mitophagy. We have presented mechanisms by which DOX compromises lysosomal acidification, integrity and chaperone-mediated autophagy through its effect on lysosome-associated and resident proteins such as LAMP, vATPase, Hsp90, Hsc70 and cathepsins. Furthermore, we have discussed novel pathways in DOX cardiotoxicity, the most prominent being DOX-induced loss of TFEB, a member of the MITF family of transcription factors, which governs lysosomal biogenesis and function. This review summarizes that in the myocardium, DOX dysregulates autophagy by impairing transcriptional factors regulating lysosomal function, thereby, precipitating proteotoxicity, mitochondrial dysfunction and cell death, thus rendering the heart susceptible to cardiomyopathic failure.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Bartlett
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada.
authors.forename: Purvi C
authors.initials: PC
authors.lastname: Trivedi
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada. Electronic address: tpulinil@dal.ca.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001343:Autophagy / Q000187:drug effects*; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism*; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000009:adverse effects*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin