Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex III.

Abstract

Recent evidence has implicated succinate-driven reverse electron transport (RET) through complex I as a major source of damaging reactive oxygen species (ROS) underlying reperfusion injury after prolonged cardiac ischemia. However, this explanation may be incomplete, because RET on reperfusion is self-limiting and therefore transient. RET can only generate ROS when mitochondria are well polarized, and it ceases when permeability transition pores (PTP) open during reperfusion. Because prolonged ischemia/reperfusion also damages electron transport complexes, we investigated whether such damage could lead to ROS production after PTP opening has occurred. Using isolated cardiac mitochondria, we demonstrate a novel mechanism by which antimycin-inhibited complex III generates significant amounts of ROS in the presence of Mg2+ and NAD+ and the absence of exogenous substrates upon inner membrane pore formation by alamethicin or Ca2+-induced PTP opening. We show that H2O2 production under these conditions is related to Mg2+-dependent NADH generation by malic enzyme. H2O2 production is blocked by stigmatellin, indicating its origin from complex III, and by piericidin, demonstrating the importance of NADH-related ubiquinone reduction for ROS production under these conditions. For maximal ROS production, the rate of NADH generation has to be equal or below that of NADH oxidation, as further increases in [NADH] elevate ubiquinol-related complex III reduction beyond the optimal range for ROS generation. These results suggest that if complex III is damaged during ischemia, PTP opening may result in succinate/malate-fueled ROS production from complex III due to activation of malic enzyme by increases in matrix [Mg2+], [NAD+], and [ADP].

• Authors: Paavo Korge, Guillaume Calmettes, Scott A John, James N Weiss
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 24 Pg. 9882-9895 (06 16 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28450391 (Publication Type: Journal Article)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Enzyme Inhibitors
• Ionophores
• Polyenes
• Pyridines
• Reactive Oxygen Species
• NAD
• antimycin
• Ubiquinone
• Alamethicin
• Adenosine Diphosphate
• Antimycin A
• piericidin A
• stigmatellin
• Hydrogen Peroxide
• Malate Dehydrogenase
• Electron Transport Complex III
• Magnesium

Topics

• Adenosine Diphosphate (metabolism)
• Alamethicin (pharmacology)
• Animals
• Antimycin A (analogs & derivatives, pharmacology)
• Biocatalysis (drug effects)
• Calcium Signaling (drug effects)
• Electron Transport Complex III (antagonists & inhibitors, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Hydrogen Peroxide (metabolism)
• Ionophores (pharmacology)
• Magnesium (metabolism)
• Malate Dehydrogenase (chemistry, metabolism)
• Mitochondria, Heart (chemistry, drug effects, metabolism)
• NAD (metabolism)
• Oxidation-Reduction
• Polyenes (pharmacology)
• Porosity (drug effects)
• Pyridines (pharmacology)
• Rabbits
• Reactive Oxygen Species (agonists, metabolism)
• Ubiquinone (metabolism)