Sirtuin-3 (SIRT3) Protein Attenuates Doxorubicin-induced Oxidative Stress and Improves Mitochondrial Respiration in H9c2 Cardiomyocytes

J Biol Chem. 2015 Apr 24;290(17):10981-93. doi: 10.1074/jbc.M114.607960. Epub 2015 Mar 10.


Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electron transfer resulting in the production of reactive oxygen species (ROS). Sirtuin-3 (SIRT3) is a class III lysine deacetylase that is localized to the mitochondria and regulates mitochondrial respiration and oxidative stress resistance enzymes such as superoxide dismutase-2 (SOD2). The purpose of this study was to determine whether SIRT3 prevents DOX-induced mitochondrial ROS production. Administration of DOX to mice suppressed cardiac SIRT3 expression, and DOX induced a dose-dependent decrease in SIRT3 and SOD2 expression in H9c2 cardiomyocytes. SIRT3-null mouse embryonic fibroblasts produced significantly more ROS in the presence of DOX compared with wild-type cells. Overexpression of wild-type SIRT3 increased cardiolipin levels and rescued mitochondrial respiration and SOD2 expression in DOX-treated H9c2 cardiomyocytes and attenuated the amount of ROS produced following DOX treatment. These effects were absent when a deacetylase-deficient SIRT3 was expressed in H9c2 cells. Our results suggest that overexpression of SIRT3 attenuates DOX-induced ROS production, and this may involve increased SOD2 expression and improved mitochondrial bioenergetics. SIRT3 activation could be a potential therapy for DOX-induced cardiac dysfunction.

Keywords: Cardiomyocyte; Heart Failure; Mitochondria; Reactive Oxygen Species (ROS); Sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / pharmacology
  • Cardiolipins / genetics
  • Cardiolipins / metabolism
  • Cell Line
  • Doxorubicin / adverse effects*
  • Doxorubicin / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Heart Diseases / chemically induced
  • Heart Diseases / enzymology
  • Heart Diseases / genetics
  • Heart Diseases / pathology
  • Mice
  • Mitochondria, Heart / metabolism*
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Oxygen Consumption / drug effects*
  • Oxygen Consumption / genetics
  • Rats
  • Reactive Oxygen Species / metabolism
  • Sirtuin 3 / biosynthesis*
  • Sirtuin 3 / genetics
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics


  • Antibiotics, Antineoplastic
  • Cardiolipins
  • Reactive Oxygen Species
  • Sirt3 protein, mouse
  • Doxorubicin
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Sirtuin 3