Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain.

Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies.

Cyanide Insensitive Oxidase Confers Hydrogen Sulfide and Nitric Oxide Tolerance to Aerobic Respiration.

Hydrogen sulfide (HS) and nitric oxide (NO) are long-known inhibitors of terminal oxidases in the respiratory chain. Yet, they exert pivotal signaling roles in physiological processes, and in several bacterial pathogens have been reported to confer resistance against oxidative stress, host immune responses, and antibiotics. , an opportunistic pathogen causing life-threatening infections that are difficult to eradicate, has a highly branched respiratory chain including four terminal oxidases of the haem-copper type (, , , and ) and one oxidase of the -type (cyanide-insensitive oxidase, CIO).

Hydrogen sulfide production does not affect antibiotic resistance in .

Hydrogen sulfide (HS) has been proposed to protect bacteria from antibiotics, pointing to HS-producing enzymes as possible targets for the development of antibiotic adjuvants. Here, MIC assays performed with mutants producing altered HS levels demonstrate that HS does not affect antibiotic resistance in this bacterium. Moreover, correlation analyses in a large collection of cystic fibrosis isolates argue against the protective role of HS from antibiotic activity during chronic lung infection.

Membrane-Bound Redox Enzyme Cytochrome -I Promotes Carbon Monoxide-Resistant Growth and Respiration.

The terminal oxidases of bacterial aerobic respiratory chains are redox-active electrogenic enzymes that catalyze the four-electron reduction of O to 2HO taking out electrons from quinol or cytochrome . Living bacteria often deal with carbon monoxide (CO) which can act as both a signaling molecule and a poison. Bacterial terminal oxidases contain hemes; therefore, they are potential targets for CO.

The terminal oxidase cytochrome bd-I confers carbon monoxide resistance to Escherichia coli cells.

Carbon monoxide (CO) plays a multifaceted role in the physiology of organisms, from poison to signaling molecule. Heme proteins, including terminal oxidases, are plausible CO targets. Three quinol oxidases terminate the branched aerobic respiratory chain of Escherichia coli.

Preparations of Terminal Oxidase Cytochrome bd-II Isolated from Escherichia coli Reveal Significant Hydrogen Peroxide Scavenging Activity.

Cytochrome bd-II is one of the three terminal quinol oxidases of the aerobic respiratory chain of Escherichia coli. Preparations of the detergent-solubilized untagged bd-II oxidase isolated from the bacterium were shown to scavenge hydrogen peroxide (H2O2) with high rate producing molecular oxygen (O). Addition of H2O2 to the same buffer that does not contain enzyme or contains thermally denatured cytochrome bd-II does not lead to any O2 production.

Bioenergetics and Reactive Nitrogen Species in Bacteria.

The production of reactive nitrogen species (RNS) by the innate immune system is part of the host's defense against invading pathogenic bacteria. In this review, we summarize recent studies on the molecular basis of the effects of nitric oxide and peroxynitrite on microbial respiration and energy conservation. We discuss possible molecular mechanisms underlying RNS resistance in bacteria mediated by unique respiratory oxygen reductases, the mycobacterial - supercomplex, and -type cytochromes.

Impact of Hydrogen Sulfide on Mitochondrial and Bacterial Bioenergetics.

This review focuses on the effects of hydrogen sulfide (HS) on the unique bioenergetic molecular machines in mitochondria and bacteria-the protein complexes of electron transport chains and associated enzymes. HS, along with nitric oxide and carbon monoxide, belongs to the class of endogenous gaseous signaling molecules. This compound plays critical roles in physiology and pathophysiology.

ROS Defense Systems and Terminal Oxidases in Bacteria.

Reactive oxygen species (ROS) comprise the superoxide anion (O), hydrogen peroxide (HO), hydroxyl radical (OH), and singlet oxygen (O). ROS can damage a variety of macromolecules, including DNA, RNA, proteins, and lipids, and compromise cell viability. To prevent or reduce ROS-induced oxidative stress, bacteria utilize different ROS defense mechanisms, of which ROS scavenging enzymes, such as superoxide dismutases, catalases, and peroxidases, are the best characterized.

Terminal Oxidase Cytochrome bd Protects Bacteria Against Hydrogen Sulfide Toxicity.

Hydrogen sulfide (H2S) is often called the third gasotransmitter (after nitric oxide and carbon monoxide), or endogenous gaseous signaling molecule. This compound plays important roles in organisms from different taxonomic groups, from bacteria to animals and humans. In mammalian cells, H2S has a cytoprotective effect at nanomolar concentrations, but becomes cytotoxic at higher concentrations.

In Ammonia Inhibits Cytochrome But Activates Cytochrome -I.

Interaction of two redox enzymes of , cytochrome and cytochrome -I, with ammonium sulfate/ammonia at pH 7.0 and 8.3 was studied using high-resolution respirometry and absorption spectroscopy.

The multifaceted roles of sulfane sulfur species in cancer-associated processes.

Sulfane sulfur species comprise a variety of biologically relevant hydrogen sulfide (HS)-derived species, including per- and poly-sulfidated low molecular weight compounds and proteins. A growing body of evidence suggests that HS, currently recognized as a key signaling molecule in human physiology and pathophysiology, plays an important role in cancer biology by modulating cell bioenergetics and contributing to metabolic reprogramming. This is accomplished through functional modulation of target proteins via HS binding to heme iron centers or HS-mediated reversible per- or poly-sulfidation of specific cysteine residues.

Nitric Oxide Does Not Inhibit but Is Metabolized by the Cytochrome - Supercomplex.

Nitric oxide (NO) is a well-known active site ligand and inhibitor of respiratory terminal oxidases. Here, we investigated the interaction of NO with a purified chimeric - supercomplex composed of cytochrome and -type terminal oxidase. Strikingly, we found that the enzyme in turnover with O and reductants is resistant to inhibition by the ligand, being able to metabolize NO at 25 °C with an apparent turnover number as high as ≈303 mol NO (mol enzyme) min at 30 µM NO.

Bacterial Oxidases of the Cytochrome Family: Redox Enzymes of Unique Structure, Function, and Utility As Drug Targets.

Cytochrome is a ubiquinol:oxygen oxidoreductase of many prokaryotic respiratory chains with a unique structure and functional characteristics. Its primary role is to couple the reduction of molecular oxygen, even at submicromolar concentrations, to water with the generation of a proton motive force used for adenosine triphosphate production. Cytochrome is found in many bacterial pathogens and, surprisingly, in bacteria formally denoted as anaerobes.

In the respiratory chain of Escherichia coli cytochromes bd-I and bd-II are more sensitive to carbon monoxide inhibition than cytochrome bo.

Bacteria can not only encounter carbon monoxide (CO) in their habitats but also produce the gas endogenously. Bacterial respiratory oxidases, thus, represent possible targets for CO. Accordingly, host macrophages were proposed to produce CO and release it into the surrounding microenvironment to sense viable bacteria through a mechanism that in Escherichia (E.

-Acetylcysteine Serves as Substrate of 3-Mercaptopyruvate Sulfurtransferase and Stimulates Sulfide Metabolism in Colon Cancer Cells.

Hydrogen sulfide (HS) is an endogenously produced signaling molecule. The enzymes 3-mercaptopyruvate sulfurtransferase (MST), partly localized in mitochondria, and the inner mitochondrial membrane-associated sulfide:quinone oxidoreductase (SQR), besides being respectively involved in the synthesis and catabolism of HS, generate sulfane sulfur species such as persulfides and polysulfides, currently recognized as mediating some of the HS biological effects. Reprogramming of HS metabolism was reported to support cellular proliferation and energy metabolism in cancer cells.

Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia.

Hydrogen sulfide (HS), a known inhibitor of cytochrome oxidase (CcOX), plays a key signaling role in human (patho)physiology. HS is synthesized endogenously and mainly metabolized by a mitochondrial sulfide-oxidizing pathway including sulfide:quinone oxidoreductase (SQR), whereby HS-derived electrons are injected into the respiratory chain stimulating O consumption and ATP synthesis. Under hypoxic conditions, HS has higher stability and is synthesized at higher levels with protective effects for the cell.

Nitrosative stress defences of the enterohepatic pathogenic bacterium Helicobacter pullorum.

Helicobacter pullorum is an avian bacterium that causes gastroenteritis, intestinal bowel and hepatobiliary diseases in humans. Although H. pullorum has been shown to activate the mammalian innate immunity with release of nitric oxide (NO), the proteins that afford protection against NO and reactive nitrogen species (RNS) remain unknown.

Cytochrome bd and Gaseous Ligands in Bacterial Physiology.

Cytochrome bd is a unique prokaryotic respiratory terminal oxidase that does not belong to the extensively investigated family of haem-copper oxidases (HCOs). The enzyme catalyses the four-electron reduction of O to 2HO, using quinols as physiological reducing substrates. The reaction is electrogenic and cytochrome bd therefore sustains bacterial energy metabolism by contributing to maintain the transmembrane proton motive force required for ATP synthesis.

Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions.

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose.

Bioenergetic relevance of hydrogen sulfide and the interplay between gasotransmitters at human cystathionine β-synthase.

Merely considered as a toxic gas in the past, hydrogen sulfide (H2S) is currently viewed as the third 'gasotransmitter' in addition to nitric oxide (NO) and carbon monoxide (CO), playing a key signalling role in human (patho)physiology. H2S can either act as a substrate or, similarly to CO and NO, an inhibitor of mitochondrial respiration, in the latter case by targeting cytochrome c oxidase (CcOX). The impact of H(2)S on mitochondrial energy metabolism crucially depends on the bioavailability of this gaseous molecule and its interplay with the other two gasotransmitters.

The Terminal Oxidase Cytochrome bd Promotes Sulfide-resistant Bacterial Respiration and Growth.

Hydrogen sulfide (H2S) impairs mitochondrial respiration by potently inhibiting the heme-copper cytochrome c oxidase. Since many prokaryotes, including Escherichia (E.) coli, generate H2S and encounter high H2S levels particularly in the human gut, herein we tested whether bacteria can sustain sulfide-resistant O2-dependent respiration.

Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber's Hereditary Optic Neuropathy Cells.

Here we have collected evidence suggesting that chronic changes in the NO homeostasis and the rise of reactive oxygen species bioavailability can contribute to cell dysfunction in Leber's hereditary optic neuropathy (LHON) patients. We report that peripheral blood mononuclear cells (PBMCs), derived from a female LHON patient with bilateral reduced vision and carrying the pathogenic mutation 11778/ND4, display increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as revealed by flow cytometry, fluorometric measurements of nitrite/nitrate, and 3-nitrotyrosine immunodetection. Moreover, viability assays with the tetrazolium dye MTT showed that lymphoblasts from the same patient are more sensitive to prolonged NO exposure, leading to cell death.

Antioxidant defence systems in the protozoan pathogen Giardia intestinalis.

The microaerophilic protist Giardia intestinalis is the causative agent of giardiasis, one of the most common intestinal infectious diseases worldwide. The pathogen lacks not only respiratory terminal oxidases (being amitochondriate), but also several conventional antioxidant enzymes, including catalase, superoxide dismutase and glutathione peroxidase. In spite of this, since living attached to the mucosa of the proximal small intestine, the parasite should rely on an efficient antioxidant system to survive the oxidative and nitrosative stress conditions found in this tract of the human gut.