Mitochondrial Redox Signaling: Interaction of Mitochondrial Reactive Oxygen Species with Other Sources of Oxidative Stress

Abstract

Significance: Oxidative stress is a well established hallmark of cardiovascular disease and there is strong evidence for a causal role of reactive oxygen and nitrogen species (RONS) therein. Recent Advances: Improvement of cardiovascular complications by genetic deletion of RONS producing enzymes and overexpression of RONS degrading enzymes proved the involvement of these species in cardiovascular disease at a molecular level. Vice versa, overexpression of RONS producing enzymes as well as deletion of antioxidant enzymes was demonstrated to aggravate cardiovascular complications. Critical Issues: With the present overview we present and discuss different pathways how mitochondrial RONS interact (crosstalk) with other sources of oxidative stress, namely NADPH oxidases, xanthine oxidase and an uncoupled nitric oxide synthase. The potential mechanisms of how this crosstalk proceeds are discussed in detail. Several examples from the literature are summarized (including hypoxia, angiotensin II mediated vascular dysfunction, cellular starvation, nitrate tolerance, aging, hyperglycemia, b-amyloid stress and others) and the underlying mechanisms are put together to a more general concept of redox-based activation of different sources of RONS via enzyme-specific ''redox switches''. Mitochondria play a key role in this concept providing redox triggers for oxidative damage in the cardiovascular system but also act as amplifiers to increase the burden of oxidative stress. Future Directions: Based on these considerations, the characterization of the role of mitochondrial RONS formation in cardiac disease as well as inflammatory processes but also the role of mitochondria as potential therapeutic targets in these pathophysiological states should be addressed in more detail in the future. Antioxid. Redox Signal. 20,[308][309][310][311][312][313][314][315][316][317][318][319][320][321][322][323][324]

Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

“…Therefore, adverse phosphorylation pattern and S-glutathionylation processes, but also oxidative depletion of BH 4 or RONS-induced augmentation of the plasma levels of asymmetrical dimethylarginine, cause the so-called redox switch within eNOS that may be mediated by the increased peroxynitrite formation observed, in particular, in GPx-1 deficiency per se or the aging vasculature, in general. 19,20 The protective effects of sepiapterin observed here support a role of BH 4 deficiency for eNOS uncoupling and dysfunction in aged animals, especially in GPx-1 deficiency. Prevention of eNOS uncoupling by Nox inhibition is compatible with the suppression of oxidative depletion of BH 4 but also of protein kinase C and protein tyrosine kinase 2 activation and of eNOS S-glutathionylation as recently shown for p47 phox and gp91 phox deficiency.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Thus, further investigations are needed to identify the localization of NOX4 and the potential cross-talk between mitochondria and NADPH oxidase. A dysregulation in this relationship may drive the vicious feed-forward cycle of ROS accumulation that can enhance inflammatory response in different diseases (96,380).…”

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

“…HPLC-based detection of extracellular hydrogen peroxide from cells and tissues can be established by the conversion of Amplex® red to resorufin in the presence of horseradish peroxidase (HRP), as already used in our group for isolated aortic ring segments and isolated immune cells [63]. The knowledge of superoxide formation in each compartment is essential, not only since subcellular sources contribute differently to various disease but there is also a vital crosstalk between reactive oxygen species from different subcellular sources [143]. Upon successful set-up of HPLC-based assays, these methods can be transferred to fluorescence plate reader-based detection of hydrogen peroxide by Amplex® red/horseradish peroxidase (AR/HRP), peroxynitrite by coumarin-7-boronic acid (CBA), oxidative nitrosation by diaminofluorescein or diaminorhodamine (DAF, DAR)-based probes [144,145] and superoxide by DHE and analogs [146] in order to establish high throughput techniques.…”