NDLI: Removal of $H_{2}O_{2}$ and generation of superoxide radical: Role of cytochrome c and NADH

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Velayutham, Murugesan Hemann, Craig Zweier, Jay L.
Description	Country affiliation: United States Author Affiliation: Velayutham M ( Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA. Murugesan.Velayutham@osumc.edu)
Abstract	In cells, mitochondria, endoplasmic reticulum, and peroxisomes are the major sources of reactive oxygen species (ROS) under physiological and pathophysiological conditions. Cytochrome c (cyt c) is known to participate in mitochondrial electron transport and has antioxidant and peroxidase activities. Under oxidative or nitrative stress, the peroxidase activity of Fe³âºcyt c is increased. The level of NADH is also increased under pathophysiological conditions such as ischemia and diabetes and a concurrent increase in hydrogen peroxide (H2O2) production occurs. Studies were performed to understand the related mechanisms of radical generation and NADH oxidation by Fe³âºcyt c in the presence of H2O2. Electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were performed with NADH, Fe³âºcyt c, and H2O2 in the presence of methyl-ß-cyclodextrin. An EPR spectrum corresponding to the superoxide radical adduct of DMPO encapsulated in methyl-ß-cyclodextrin was obtained. This EPR signal was quenched by the addition of the superoxide scavenging enzyme Cu,Zn-superoxide dismutase (SOD1). The amount of superoxide radical adduct formed from the oxidation of NADH by the peroxidase activity of Fe³âºcyt c increased with NADH and H2O2 concentration. From these results, we propose a mechanism in which the peroxidase activity of Fe³âºcyt c oxidizes NADH to NAD(â¢), which in turn donates an electron to O2, resulting in superoxide radical formation. A UV-visible spectroscopic study shows that Fe³âºcyt c is reduced in the presence of both NADH and H2O2. Our results suggest that Fe³âºcyt c could have a novel role in the deleterious effects of ischemia/reperfusion and diabetes due to increased production of superoxide radical. In addition, Fe³âºcyt c may play a key role in the mitochondrial 'ROS-induced ROS-release' signaling and in mitochondrial and cellular injury/death. The increased oxidation of NADH and generation of superoxide radical by this mechanism may have implications for the regulation of apoptotic cell death, endothelial dysfunction, and neurological diseases. We also propose an alternative electron transfer pathway, which may protect mitochondria and mitochondrial proteins from oxidative damage.
File Format	HTM / HTML
ISSN	08915849
e-ISSN	18734596
DOI	10.1016/j.freeradbiomed.2011.04.007
Journal	Free Radical Biology and Medicine
Issue Number	1
Volume Number	51
Language	English
Publisher	Elsevier
Publisher Date	2011-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Free radicals biology Cytochromes c Metabolism Hydrogen Peroxide Chemistry Nad Superoxides Animals Cyclic N-oxides Electron Spin Resonance Spectroscopy Electron Transport Horses Mitochondria Oxygen Reactive Oxygen Species Spin Trapping Superoxide Dismutase Beta-cyclodextrins Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Physiology (medical) Biochemistry

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