Superoxide is the major reactive oxygen species regulating autophagy.

Abstract

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.

• Authors: Y Chen, M B Azad, S B Gibson
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 16 Issue 7 Pg. 1040-52 (Jul 2009) ISSN: 1476-5403 [Electronic] England
• PMID: 19407826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antioxidants
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• Oxidants
• RNA, Small Interfering
• Reactive Oxygen Species
• Superoxides
• Estradiol
• 2-Methoxyestradiol
• Hydrogen Peroxide
• Catalase
• Superoxide Dismutase
• Atg7 protein, human
• Autophagy-Related Protein 7
• Ubiquitin-Activating Enzymes

Topics

• 2-Methoxyestradiol
• Antioxidants (pharmacology)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects, physiology)
• Autophagy-Related Protein 7
• Beclin-1
• Catalase (pharmacology)
• Cell Line
• Cell Line, Tumor
• Estradiol (analogs & derivatives, pharmacology)
• HeLa Cells
• Humans
• Hydrogen Peroxide (metabolism, pharmacology)
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Oxidants (metabolism, pharmacology)
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (antagonists & inhibitors, genetics, metabolism)
• Superoxides (metabolism)
• Ubiquitin-Activating Enzymes (genetics, metabolism)