Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q

Biophys J. 2009 Feb 18;96(4):1388-98. doi: 10.1016/j.bpj.2008.10.042.


Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Body Weight / drug effects
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / physiopathology
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / therapeutic use
  • Doxorubicin / pharmacology*
  • Doxorubicin / toxicity
  • Electron Spin Resonance Spectroscopy
  • Electron Transport Complex IV / metabolism*
  • Endomyocardial Fibrosis / drug therapy
  • Heart / drug effects
  • Heart / physiology
  • Heme / physiology
  • Male
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / enzymology
  • Myocardium / enzymology*
  • Organophosphorus Compounds / pharmacology*
  • Organophosphorus Compounds / therapeutic use
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquinone / pharmacology*
  • Ubiquinone / therapeutic use


  • Cardiotonic Agents
  • Organophosphorus Compounds
  • Ubiquinone
  • Heme
  • mitoquinone
  • Doxorubicin
  • Electron Transport Complex IV