title: Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice.
abstract: Doxorubicin (Doxo) is a chemotherapeutic drug widely used to treat variety of cancers. One of the most serious side effects of Doxo is its dose-dependent and delayed toxicity to the heart. Doxo is known to induce cardiac mitochondrial damage. Recently, the mitochondrial sirtuin SIRT3 has been shown to protect mitochondria from oxidative stress. Here we show that overexpression of SIRT3 protects the heart from toxicity of Doxo by preventing the drug-induced mitochondrial DNA (mtDNA) damage. Doxo treatment caused depletion of Sirt3 levels both in primary cultures of cardiomyocytes and in mouse hearts, which led to massive acetylation of mitochondrial proteins. Doxo-induced toxicity to cardiomyocytes was associated with increased reactive oxygen species (ROS) production, mitochondrial fragmentation, and cell death. Overexpression of SIRT3 helped to attenuate Doxo-induced ROS levels and cardiomyocyte death. Sirt3 knockout (Sirt3.KO) mice could not endure the full dose of Doxo treatment, developed exacerbated cardiac hypertrophy, and died during the course of treatment, whereas Sirt3 transgenic (Sirt3.tg) mice were protected against Doxo-induced cardiotoxicity. Along with Sirt3, we also observed a concomitant decrease in levels of oxoguanine-DNA glycosylase-1 (OGG1), a major DNA glycosylase that hydrolyzes oxidized-guanine (8-oxo-dG) to guanine. Depletion of OGG1 levels was associated with increased mtDNA damage. Sirt3.KO mice and Doxo-treated mice showed increased 8-oxo-dG adducts in DNA and corresponding increase in mtDNA damage, whereas, 8-oxo-dG adducts and mtDNA damage were markedly reduced in Sirt3 overexpressing transgenic mice hearts. These results thus demonstrated that Sirt3 activation protects the heart from Doxo-induced cardiotoxicity by maintaining OGG1 levels and protecting mitochondria from DNA damage.
authors.affiliation: Department of Surgery, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois;
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.affiliation: Department of Surgery, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois;
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.affiliation: Department Medicine, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois; and.
authors.forename: Will
authors.initials: W
authors.lastname: Sharp
authors.affiliation: Department Medicine, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois; and.
authors.forename: Yong Hu
authors.initials: YH
authors.lastname: Fang
authors.affiliation: Department Medicine, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois; and.
authors.forename: Gene
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois mgupta@surgery.bsd.uchicago.edu.
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Surgery, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois;
authors.forename: Sadhana
authors.initials: S
authors.lastname: Samant
authors.affiliation: Department of Surgery, Committee on Molecular Pathogenesis and Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois;
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006868:Hydrolysis; D008297:Male; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism; D013997:Time Factors
chemical_list: D018736:DNA Adducts; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; C000607791:SIRT3 protein, rat; C525046:Sirt3 protein, mouse; D004317:Doxorubicin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D056566:Sirtuin 3; D037761:Sirtuins; D003849:Deoxyguanosine
keywords: ROS; Sirt3; doxorubicin; mitochondria