Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase

Abstract

Reactive oxygen species (ROS) are associated with a number of mitochondrial disorders. These include: ischemia/reperfusion injury, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, and other age-related degenerative changes. ROS can be generated at numerous sites within the cell, but the mitochondrial electron transport chain is recognized as the major source of intracellular ROS. Two mitochondrial electron-transfer complexes are major sources of ROS: complex I and complex III. Oxidative damage to either of these complexes, or to electron transport complexes that are in close proximity to these ROS sources, e.g., cytochrome c oxidase, would be expected to inhibit electron transport. Such inhibition would lead to increased electron leakage and more ROS production, much like the well-known effect of adding electron transport inhibitors. Recent studies reveal that ROS and lipid peroxidation products are effective inhibitors of the electron-transport complexes. In some cases, inactivation of enzymes correlates with chemical modification of only a small number of unusually reactive amino acids. In this article, we review current knowledge of ROS-induced alterations within three complexes: (1) complex IV; (2) complex III; and (3) complex I. Our goal is to identify "hot spots" within each complex that are easily chemically modified and could be responsible for ROS-induced inhibition of the individual complexes. Special attention has been placed on ROS-induced damage to cardiolipin that is tightly bound to each of the inner membrane protein complexes. Peroxidation of the bound cardiolipin is thought to be particularly important since its close proximity and long residence time on the protein make it an especially effective reagent for subsequent ROS-induced damage to these proteins.

Phenotypic Screening of a Targeted Mutant Library Reveals Campylobacter jejuni Defenses against Oxidative Stress

“…Therefore, ETC disturbance may cause increased production of ROS through electron leakage, leading to the observed hypersensitive phenotype of the flagellum mutants. It has been well documented that electron leakage at complexes I and III of the ETC lead to the endogenous production of superoxide (26). Disruption of proton/electron flow could also lead to the production of harmful oxy-intermediates and free radicals at complex IV (cytochrome c oxidase), which is the only ETC complex that directly interacts with molecular oxygen (26).…”

“…It has been well documented that electron leakage at complexes I and III of the ETC lead to the endogenous production of superoxide (26). Disruption of proton/electron flow could also lead to the production of harmful oxy-intermediates and free radicals at complex IV (cytochrome c oxidase), which is the only ETC complex that directly interacts with molecular oxygen (26). To test this hypothesis, we assessed the oxidant sensitivity of the flagellar mutants in the presence of an alternative terminal electron acceptor, fumarate.…”

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

“…Damage to complex I, the most vulnerable ETC complex, increases ROS production, which leads to a vicious circle of further mitochondrial dysfunction. It is important to note that damage to complex I has a stronger impact on mitochondrial function than damage to other complexes, as mitochondria possess smaller amounts of complex I than other ETC complexes (212). Finally, it is known that phospholipids that integrate mitochondrial membranes are rich in unsaturated fatty acids, which are extremely vulnerable to lipid peroxidation by ROS.…”

The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

“…LYCAT is a key enzyme that regulates the unique C18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin necessary for binding to mitochondrial proteins, such as cytochrome C, and therefore is critical for normal mitochondrial electron transport and function (19,20). Additionally, LYCAT regulates hematopoietic and endothelial lineages suggesting a potential role in vascular development (21).…”