QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online November 21, 2007
doi: 10.1242/10.1242/jcs.011163

This Article Figures Only Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Gibson, S. B. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Gibson, S. B.

Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species

¹ Manitoba Institute of Cell Biology, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada
² Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
³ CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada
⁴ Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

^* Author for correspondence (e-mail: gibsonsb{at}cc.umanitoba.ca)

Accepted 20 September 2007

Autophagy is a self-digestion process important for cell survival during starvation. It has also been described as a form of programmed cell death. Mitochondria are important regulators of autophagy-induced cell death and damaged mitochondria are often degraded by autophagosomes. Inhibition of the mitochondrial electron transport chain (mETC) induces cell death through generating reactive oxygen species (ROS). The role of mETC inhibitors in autophagy-induced cell death is unknown. Herein, we determined that inhibitors of complex I (rotenone) and complex II (TTFA) induce cell death and autophagy in the transformed cell line HEK 293, and in cancer cell lines U87 and HeLa. Blocking the expression of autophagic genes (beclin 1 and ATG5) by siRNAs or using the autophagy inhibitor 3-methyladenine (3-MA) decreased cell death that was induced by rotenone or TTFA. Rotenone and TTFA induce ROS production, and the ROS scavenger tiron decreased autophagy and cell death induced by rotenone and TTFA. Overexpression of manganese-superoxide dismutase (SOD2) in HeLa cells decreased autophagy and cell death induced by rotenone and TTFA. Furthermore, blocking SOD2 expression by siRNA in HeLa cells increased ROS generation, autophagy and cell death induced by rotenone and TTFA. Rotenone- and TTFA-induced ROS generation was not affected by 3-MA, or by beclin 1 and ATG5 siRNAs. By contrast, treatment of non-transformed primary mouse astrocytes with rotenone or TTFA failed to significantly increase levels of ROS or autophagy. These results indicate that targeting mETC complex I and II selectively induces autophagic cell death through a ROS-mediated mechanism.

Key words: Electron transport chain, Autophagic cell death, Apoptosis, Reactive oxygen species

Related articles in JCS:

Cancer cells die of consumption

JCS 2007 120: 2303. [Full Text]  

This article has been cited by other articles:

				D. Xiao, A. A. Powolny, and S. V. Singh Benzyl Isothiocyanate Targets Mitochondrial Respiratory Chain to Trigger Reactive Oxygen Species-dependent Apoptosis in Human Breast Cancer Cells J. Biol. Chem., October 31, 2008; 283(44): 30151 - 30163. [Abstract] [Full Text] [PDF]

				W.-L. Yen and D. J. Klionsky How to Live Long and Prosper: Autophagy, Mitochondria, and Aging Physiology, October 1, 2008; 23(5): 248 - 262. [Abstract] [Full Text] [PDF]

				K. Singletary and J. Milner Diet, Autophagy, and Cancer: A Review Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1596 - 1610. [Abstract] [Full Text] [PDF]