Reactive Oxygen Species in the Induction of Toxicity

Abstract

Oxidative stress is among the major causes of toxicity due to interaction of reactive oxygen species (ROS) with cellular macromolecules and structures and interference with signal transduction pathways. ROS originate from exogenous and endogenous sources; among the former are UV and ionizing radiation and xenobiotics, the latter are represented by a number of metabolic reactions. The mitochondrial respiratory chain, specially from Complexes I and III, is considered the main origin of ROS particularly under conditions of high membrane potential, but several other sources may be important for ROS generation, such as mitochondrial p66 Shc , monoamine oxidase, α‐ketoglutarate dehydrogenase and extramitochondrial xanthine oxidase, cytochrome P450, nitric oxide synthase, peroxisomal enzymes, plasma membrane NADPH oxidases, and lipoxygenase, with the participation of redox‐active metal ions. ROS are able to oxidatively modify lipids, proteins, carbohydrates and nucleic acids and to activate/inactivate signalling pathways by oxidative modification of redox‐active factors. Cells are endowed with several defence mechanisms, including repair or removal of damaged molecules, and antioxidant systems, either enzymatic or nonenzymatic. Oxidative stress is at the basis of ageing and many pathological disorders, such as ischaemic diseases, neurodegenerative diseases, diabetes and cancer, although the underlying mechanisms are not always completely understood.

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

“…However, the membrane-ETS in the mtIM is probably the major source of ROS. Other mitochondrial enzyme systems can significantly contribute to ROS generation [ 223 ], as dihydrolipoamide dehydrogenase (a subunit of the α-ketoglutarate and pyruvate dehydrogenase complexes), monoamine oxidase, mitochondrial nitric oxide synthase and the adaptor protein p66 Shc . These systems are not relevant to this review and will not be considered here.…”

“…A further consequence of SC disassembly would be CI dissociation with loss of electron transfer and/or proton translocation; the consequently altered electron transfer may result in further ROS generation. The possible severe metabolic and physiological consequences of SC dissociation are reported in the scheme in Figure 8 [ 223 ].…”

The Interplay Between Respiratory Supercomplexes and ROS in Aging

“…Among endogenous sources there are: xanthine oxidase, cytochrome P-450 enzymes in the endoplasmic reticulum, peroxisomal flavin oxidases and plasma membrane NADPH oxidases (150). Nevertheless, the mitochondrial respiratory chain in the inner mitochondrial membrane (IMM) is usually considered one of the major sources of ROS, although other enzyme systems in mitochondria can be important contributors to ROS generation (229). Among these, we mention here dihydrolipoamide dehydrogenase (a subunit of the α-ketoglutarate and pyruvate dehydrogenase complexes) (369,382,375,8,311,192,193), monoamine oxidase (46,256,85), and mitochondrial nitric oxide synthase (418).…”

Relevance of Mitochondrial Genetics and Metabolism in Cancer Development

“…These changes may have deep metabolic consequences, as depicted in the scheme in Figure 1. An initial enhanced ROS generation due to different possible reasons and originating in different districts of the cell besides mitochondria (Lenaz and Strocchi 2009) would induce supercomplex disorganization eventually leading to possible decrease of complex I assembly; both the lack of efficient electron channeling and the loss of complex I would decrease NAD-linked respiration and ATP synthesis. Here we briefly summarize the experimental evidence pertaining to this hypothesis.…”