Mitochondrial ROS and Apoptosis
Reactive oxygen species (ROS) are by-products of cellular metabolism or of xenobiotic exposure. Depending on their level, ROS can be detrimental leading to oxidative modifications in cellular lipids, proteins, or DNA or can be beneficial participating in
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Mitochondrial ROS and Apoptosis Hazem El-Osta and Magdalena L. Circu
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Reactive Oxygen Species and Mitochondrial Sources of Their Generation
The term reactive oxygen species (ROS) comprises O2-derived free forms that have accepted extra electrons and that can be free radicals like superoxide (O2•−) or hydroxyl radical (HO•) as well as O2-based nonradical species such as hydrogen peroxide (H2O2) [1]. Although H2O2 is not a free radical, it is considered a ROS because, in the presence of transition metals, it is able to form the HO• via Fenton chemistry. This hydroxyl radical is highly reactive and can damage intracellular macromolecules including proteins, lipids, and DNA [2]. O2•− is a reactive species that is converted to H2O2 by CuZn-SOD (CuZn-superoxide dismutase) in the cytosol and in the mitochondrial intermembrane space and by MnSOD in the mitochondrial matrix. Next, H2O2 is converted to oxygen and water by catalase (CAT) and glutathione peroxidase (GPx) (Fig. 1.1). Small amounts of mitochondrial H2O2 have been shown to function as a signaling molecule in the cytosol being involved in several signaling pathways associated with the cell cycle, stress response, autophagy, and redox balance [3, 4]. Locally, mitochondria-generated H2O2 is a key regulator of mitochondrial ROS level via activation of mitochondrial uncoupling proteins [5]. Although physiological concentrations of ROS can be neutralized by mitochondrial antioxidant redox systems, higher levels can become detrimental and cause irreversible oxidative damages to cellular macromolecules leading to apoptosis or necrosis. Mitochondria are the major source of ROS in the majority of eukaryotic cells. Mitochondria consume nearly 90 % of total oxygen content in the cell for oxidative
H. El-Osta, M.D. • M.L. Circu, Ph.D. (*) Department of Medicine, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA e-mail: [email protected]; [email protected] © Springer International Publishing Switzerland 2016 L.M. Buhlman (ed.), Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease, DOI 10.1007/978-3-319-42139-1_1
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H. El-Osta and M.L. Circu
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O2
é
O2•SOD Fe2+
H2O
GPxs, Prxs, CAT
H2O2
Reversible thiol oxidation
Cellular signaling
Fe3+
HO• Oxidative damages to cellular macromolecules
Apoptosis/ Necrosis
Fig. 1.1 ROS formation and ROS metabolism. Monoelectron reduction of O2 leads to the formation of superoxide anion radical (O2•−). Cellular superoxide dismutase (SOD) converts O2•− to H2O2, a nonradical ROS. H2O2 is reduced to water by several cellular enzymes including glutathione peroxidase (Gpx), peroxiredoxins (Prx), and catalase (CAT). In the presence of transition metals, H2O2 can form hydroxyl radical via Fenton chemistry, a toxic species that causes oxidative modifications to cellular macromolecules. Similarly, high amounts of H2O2 can damage proteins, lipids, or DNA leading to oxidative stress-induced necrosis or apoptosis. Conversely, small amounts of H2O2 can function in c
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