Review ArticlesMitochondrial damage induced by conditions of oxidative stress
Introduction
Reactive oxygen species (ROS) may lead to the oxidative damage of virtually any biomolecule. Mitochondria are particularly susceptible to damage induced by ROS, which are generated continuously by the mitochondrial respiratory chain [1], [2]. Mitochondria are also a major site for the accumulation of low molecular weight Fe2+ complexes, which promote the oxidative damage of membrane lipids [3], [4], [5], [6]. Recently, a large number of studies have associated mitochondrial dysfunction caused by ROS to both accidental cell death (necrosis) and programmed cell death (apoptosis; see refs. [7], [8], [9], [10]). This article concentrates on the mechanisms of mitochondrial ROS generation as well as the effects of ROS on mitochondrial components and function.
Section snippets
Mitochondrial generation of reactive oxygen species
In normal mitochondria, oxygen is reduced to water by cytochrome c oxidase in four consecutive one-electron steps, because molecular oxygen possesses a triplet state configuration. Release of partially reduced oxygen intermediates does not occur during this process because of the high binding affinity of cytochrome c (for review, see ref. [2]). Thus, production of superoxide radicals (O2•−) through monoelectronic reduction of O2 at the level of cytochrome c oxidase is practically nonexistent.
Mitochondrial membrane protein oxidation and permeability transition
The total mitochondrial membrane protein content, including both the inner and outer membranes, varies between 60 and 65%, while the inner membrane protein content is believed to be as high as 75% [14]. Because of the high protein content of the inner membrane, it is expected that these proteins are one of the primary targets of mitochondrial-generated ROS. Indeed, membrane protein thiol groups suffer extensive oxidation in conditions of Ca2+-induced mitochondrial oxidative stress [26], [32],
Mitochondrial membrane lipid peroxidation
Lipid peroxidation, one of the main oxidative alterations of biological membranes, can be induced by many different oxidizing agents [75], [76]. This process is initiated by a free radical, which abstracts a hydrogen atom from unsaturated fatty acids of the membrane, leading to the generation of lipid radicals, which then combine with molecular oxygen (L → LOO). The radicals formed then propagate the chain of lipid peroxidation, which is stopped by the reaction between two lipid radicals or by
Damage to mitochondrial DNA
Mitochondrial DNA (mtDNA) is attached to the inner mitochondrial membrane and is particularly prone to oxidative damage due both to its lack of protective histones and proofreading and to the presence of incomplete repair mechanisms [88], [89], [90]. Indeed, mtDNA fragmentation seems to be closely related to cellular damage associated with aging [91], [92], [93]. Because mtDNA encodes for essential proteins involved in the process of oxidative phosphorylation, this fragmentation leads to
Mitochondrial damage in accidental and programmed cell death — necrosis and apoptosis
When a cell is submitted to a damaging situation severe enough to promote irreversible dysfunction of essential cellular components, it undergoes accidental cell death, or necrosis. On the other hand, most cells have mechanisms that permit them to die (or commit cell “suicide”) even under situations in which cellular components are not irreversibly damaged. This form of programmed cell death is termed apoptosis (for review, see ref. [94]). Apoptosis is a well defined process in which cell
Conclusions
Mitochondrial oxidative damage resulting from oxidative stress of the organelle has been demonstrated to participate in the mechanisms of both accidental and programmed cell death. A better understanding of the mechanisms by which mitochondria generate and detoxify ROS, as well as the consequences of mitochondrial oxidative stress, will surely contribute to the development of more efficient therapies to inhibit unwanted cell death in these situations, and may provide better treatment for a
Acknowledgements
Acknowledgements — The work of this laboratory was supported by grants from the Brazilian Agencies FAPESP, FAEP-UNICAMP, CNPq-PADCT and PRONEX. A. J. K. is supported by a FAPESP scholarship.
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Alicia J. Kowaltowski is a doctoral student of professor A. E. Vercesi, dedicated to the study of mitochondrial oxidative stress since 1993. She graduated as an M.D. at the State University of Campinas in 1997.
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Anibal E. Vercesi is an M.D. graduated in the State University of Campinas in 1972. He received his doctorate in Biochemistry in the same institution in 1974, and performed his postdoctoral work under the supervision of Professor Albert L. Lehningher, between 1980 and 1981. He is currently a full professor in the Department of Clinical Pathology in the State University of Campinas School of Medicine, Brazil and a Adjunct Professor of Microbiology in the Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana, Illinois, USA. His main areas of interest are mitochondrial bioenergetics and oxidative stress.