Changes in mitochondrial redox state, membrane potential and calcium precede mitochondrial dysfunction in doxorubicin-induced cell death

Biochim Biophys Acta. 2011 Jun;1813(6):1144-52. doi: 10.1016/j.bbamcr.2011.03.002. Epub 2011 Mar 21.


Mitochondria play central roles in cell life as a source of energy and in cell death by inducing apoptosis. Many important functions of mitochondria change in cancer, and these organelles can be a target of chemotherapy. The widely used anticancer drug doxorubicin (DOX) causes cell death, inhibition of cell cycle/proliferation and mitochondrial impairment. However, the mechanism of such impairment is not completely understood. In our study we used confocal and two-photon fluorescence imaging together with enzymatic and respirometric analysis to study short- and long-term effects of doxorubicin on mitochondria in various human carcinoma cells. We show that short-term (<30 min) effects include i) rapid changes in mitochondrial redox potentials towards a more oxidized state (flavoproteins and NADH), ii) mitochondrial depolarization, iii) elevated matrix calcium levels, and iv) mitochondrial ROS production, demonstrating a complex pattern of mitochondrial alterations. Significant inhibition of mitochondrial endogenous and uncoupled respiration, ATP depletion and changes in the activities of marker enzymes were observed after 48 h of DOX treatment (long-term effects) associated with cell cycle arrest and death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects*
  • Calcium / metabolism*
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Cell Survival / drug effects
  • Citrate (si)-Synthase / metabolism
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology*
  • Electron Transport Complex I / metabolism
  • HT29 Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects*
  • Microscopy, Confocal
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Oxidation-Reduction / drug effects
  • Reactive Oxygen Species / metabolism
  • Time Factors
  • Uncoupling Agents / pharmacology


  • Antibiotics, Antineoplastic
  • Reactive Oxygen Species
  • Uncoupling Agents
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Doxorubicin
  • Adenosine Triphosphate
  • Citrate (si)-Synthase
  • Electron Transport Complex I
  • Calcium