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Review
. 2022 Jun 22;11(13):2000.
doi: 10.3390/cells11132000.

Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay

Leonardo Schirone  1 , Luca D'Ambrosio  1 , Maurizio Forte  2 , Riccardo Genovese  1 , Sonia Schiavon  1 , Giulia Spinosa  1 , Giuliano Iacovone  3 , Valentina Valenti  3 , Giacomo Frati  1   2 , Sebastiano Sciarretta  1   2
Affiliations
Review

Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay

Leonardo Schirone et al. Cells. .

Abstract

Cardiotoxicity has emerged as a major side effect of doxorubicin (DOX) treatment, affecting nearly 30% of patients within 5 years after chemotherapy. Heart failure is the first non-cancer cause of death in DOX-treated patients. Although many different molecular mechanisms explaining the cardiac derangements induced by DOX were identified in past decades, the translation to clinical practice has remained elusive to date. This review examines the current understanding of DOX-induced cardiomyopathy (DCM) with a focus on mitochondria, which were increasingly proven to be crucial determinants of DOX-induced cytotoxicity. We discuss DCM pathophysiology and epidemiology and DOX-induced detrimental effects on mitochondrial function, dynamics, biogenesis, and autophagy. Lastly, we review the current perspectives to contrast the development of DCM, which is still a relatively diffused, invalidating, and life-threatening condition for cancer survivors.

Keywords: DOX; anthracycline; cardiomyopathy; heart; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
An overview of DOX-induced cytotoxicity in cardiomyocytes. The image reports the main mechanisms mediating the harmful effects of DOX. See text for further details. AMPK = AMP-activated protein kinase; AR = adrenergic receptor; Gp130 = glycoprotein 130; HDAC = histone deacetylase; HMGB1 = high-mobility group box 1; HO-1 = heme oxygenase 1; mtDNA = mitochondrial DNA; MyD88 = myeloid differentiation primary response 88; NADP = nicotinamide adenine dinucleotide phosphate; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; NOX = NADPH oxidase; NRF2 = nuclear respiratory factor 2; PI3Kγ = phosphoinositide 3-kinase γ; sq-DOX = doxorubicin (semiquinone form); STAT3 = signal transducer and activator of transcription 3; TLR = Toll-like receptor. This illustration includes elements from Servier Medical Art.
Figure 2
Figure 2
Mitochondrial derangements in DOX-induced cardiotoxicity. ABCB8 = ATP-binding cassette sub-family B member 8; AMPK = AMP-activated protein kinase; BNIP-3 = BCL2 19 kD protein-interacting protein 3; CAT = catalase; Cyt C = cytochrome C; ETC = electron transport chain; Glu = glucose; HO-1 = heme oxygenase 1; KEAP = Kelch-like ECH-associated protein; mPTP = mitochondrial permeability transition pore; NRF2 = nuclear respiratory factor 2; PGC-1α = PPARγ coactivator 1 alpha; PPAR = peroxisome proliferator-activated receptor; ROS = reactive oxygen species; SIRT1 = sirtuin 1; TCTP = translationally controlled tumor protein; TOP1mt = mitochondrial topoisomerase 1. This illustration includes elements from Servier Medical Art.
Figure 3
Figure 3
DOX impairs mitochondrial dynamics and mitophagy through different pathways. AMPK = AMP-activated protein kinase; CBF/NF-Y = CCAAT-binding factor/nuclear factor-Y; DRP1 = dynamin-related protein 1; FoxO1 = Forkhead box protein O1; GATA4 = GATA-binding protein 4; Mfn-2 = mitofusin 2; mTOR = mechanistic target of rapamycin complex 1; PI3Kγ = phosphoinositide 3-kinase γ; PINK1 = PTEN-induced kinase 1; RAB-9 = Ras-related protein Rab-9; RIP1 = receptor-interacting protein 1; ULK1 = unc-51-like kinase 1. This illustration includes elements from Servier Medical Art.
See this image and copyright information in PMC

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