1,721,004 research outputs found
The dual function of reactive oxygen/nitrogen species in bioenergetics and cell death: The role of ATP synthase.
No full textReactive oxygen species (ROS) and reactive nitrogen species (RNS) targeting mitochondria are major causative factors in disease pathogenesis. The mitochondrial permeability transition pore (PTP) is a mega-channel modulated by calcium and ROS/RNS modifications and it has been described to play a crucial role in many pathophysiological events since prolonged channel opening causes cell death. The recent identification that dimers of ATP synthase form the PTP and the fact that posttranslational modifications caused by ROS/RNS also affect cellular bioenergetics through the modulation of ATP synthase catalysis reveal a dual function of these modifications in the cells. Here, we describe mitochondria as a major site of production and as a target of ROS/RNS and discuss the pathophysiological conditions in which oxidative and nitrosative modifications modulate the catalytic and pore-forming activities of ATP synthase
The energetic cost of NNT-dependent ROS removal
Full text linkUnder conditions of high nutrient availability and low ATP synthesis, mitochondria generate reactive oxygen species (ROS) that must be removed to avoid cell injury. Among the enzymes involved in this scavenging process, peroxidases play a crucial role, using NADPH provided mostly by nicotinamide nucleotide transhydrogenase (NNT). However, scarce information is available on how and to what extent ROS formation is linked to mitochondrial oxygen consumption. A new study by Smith et al. shows that NNT activity maintains low ROS levels by means of a fine modulation of mitochondrial oxygen utilization
β2-Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another 'radical' road to heart failure?
No full textβ2-receptors, NADPH oxidase, ROS and p38 MAPK: Another “radical” road to heart failure?
No full textPersistent activation of the cardiac β-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both β1- and β2-adrenoceptors are known to mediate these noxious effects, yet the β1-adrenoceptor-PKA axis has received greater attention with less information available on β2-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that β2-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that β2-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4
Genes, Geography and Geometry The "Critical Mass" in Hypertrophic Cardiomyopathy
No full textHCM is caused by mutations in one of a number of genes. Approximately 450 different mutations have been discovered in genes for functional/structural proteins in the sarcomere (13 related genes) and myofilaments. Most of the alterations are missense, with a single amino acid residue substituted for another. The majority of HCM molecular defects lie in genes encoding functional and regulatory sarcomeric proteins such as beta-myosin heavy chain , actin, cardiac troponin T and I, and tropomyosin, as well as structural proteins, ie, myosin binding protein C (MYBPC) and titin.2 Identifying the specific gene mutation underlying the disease in individuals has more than an etiological relevance, as specific gene mutations may contribute to the different phenotypic and functional outcomes in patients suffering from HCM
Measurement of mitochondrial ROS formation
No full textReactive oxygen species (ROS) are involved in both physiological and pathological processes. This widely accepted concept is based more on the effects of antioxidant interventions than on reliable assessments of rates and sites of intracellular ROS formation. This argument applies also to mitochondria that are generally considered the major site for ROS formation, especially in skeletal and cardiac myocytes.Detection of oxidative modifications of intracellular or circulating molecules is frequently used as a marker of ROS formation. However, this approach provides limited information on spatiotemporal aspects of ROS formation that have to be defined in order to elucidate the role of ROS in a given pathophysiological condition. This information can be obtained by means of fluorescent probes that allow monitoring ROS formation in cell-free extracts and isolated cells. Thus, this approach can be used to characterize ROS formation in both isolated mitochondria and mitochondria within intact cells. This chapter describes three major examples of the use of fluorescent probes for monitoring mitochondrial ROS formation. Detailed methods description is accompanied by a critical analysis of the limitations of each technique, highlighting the possible sources of errors in performing the assay and results interpretation
Tetrahydrobiopterin (BH4) reverses established heart failure normalizing calcium cycling at the cardiomyocytes level
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