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Rydstroem 1975 Biochem Biophys Res Commun + (Nicotinamide nucleotide transhydrogenase f … Nicotinamide nucleotide transhydrogenase from bovine heart mitochondria was solubilized with cholate and partially purified by ammoniumsulphate fractionation and density gradient centrifugation. Compared to submitochondrial particles this preparation contained less than 10% of oligomycin-sensitive ATPase and cytochromes. When reconstituted with purified mitochondrial phosphatidylcholine, the enzyme catalyzed a reduction of NAD+ by NADPH that was stimulated by uncouplers and which showed a concomitent uncoupler-sensitive uptake of the lipophilic anion tetraphenylboron, indicating the generation of a membrane potential. It is concluded that transhydrogenase can energize the vesicles directly without the intervention of ATPase or cytochromes.tly without the intervention of ATPase or cytochromes.)
Hoejeberg 1977 Biochem Biophys Res Commun + (Nicotinamide nucleotide transhydrogenase f … Nicotinamide nucleotide transhydrogenase from beef heart mitochondria was purified to homogeneity and characterized. The enzyme is devoid of other respiratory chain activities as well as flavin. Reduction of NAD+ by NADPH catalyzed by reconstituted transhydrogenase generates an uncoupler-sensitive uptake of lipophilic anions, whereas the rate of reduction of NAD+ by NADPH is enhanced about 13 fold by uncouplers. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate reveales that the protein consists of a single polypeptide of a molecular weight of 97,000. consists of a single polypeptide of a molecular weight of 97,000.)
Dall 2021 J Biol Chem + (Nicotinamide phosphoribosyltransferase (NA … Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to nicotinamide adenine dinucleotide (NAD+). As low hepatic NAD+ levels have been linked to the development of nonalcoholic fatty liver disease (NAFLD), we hypothetized that ablation of hepatic Nampt would affect susceptibility to liver injury in response to diet-induced metabolic stress. Following 3 weeks on a low-methionine, choline-free 60% high-fat diet (MCD), hepatocyte-specific Nampt knockout mice (HNKO) accumulated less triglyceride than wild-type littermates, but had increased histological scores for liver inflammation, necrosis, and fibrosis. Surprisingly, liver injury was also observed in HNKO mice on the purified control diet (PD). This HNKO phenotype was also associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in PD-fed HNKO liver. In addition, fibrotic area in HNKO liver sections negatively correlated with hepatic NAD+, and liver injury was prevented by supplementation with NAD+ precursors nicotinamide riboside (NR) and nicotinic acid. Mass spectrometry (MS)-based proteomic analysis revealed that NR supplementation rescued hepatic levels of oxidoreductase- and OXPHOS proteins. Finally, single nucleus RNAseq showed that transcriptional changes in the HNKO liver mainly occurred in hepatocytes, and changes in the hepatocyte transcriptome were associated with liver necrosis. In conclusion, HNKO livers have reduced respiratory capacity, decreased abundance of mitochondrial proteins, and are susceptible to fibrosis due to low NAD+ levels. Our data suggest a critical threshold level of hepatic NAD+ that determines the predisposition to liver injury and supports that NAD+ precursor supplementation can prevent liver injury and NAFLD progression.n to liver injury and supports that NAD+ precursor supplementation can prevent liver injury and NAFLD progression.)
Remie 2020 Am J Clin Nutr + (Nicotinamide riboside (NR) is an NAD<su … Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation.We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers.A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism.Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.small>Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)
Torres 2016 Redox Biol + (Niemann Pick type C (NPC) disease is a pro … Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.ion with other options. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
Korsten 2010 Biochim Biophys Acta + (Ninety-five percent of Leber hereditary op … Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON expression, complex I- and complex II-dependent adenosine triphosphate synthesis rates (CI-ATP, CII-ATP) were determined in digitonin-permeabilized peripheral blood mononuclear cells (PBMCs) of thirteen healthy controls and for each primary mutation of a minimum of three unrelated patients and of three unrelated carriers with normal vision and were normalized per mitochondrion (citrate synthase activity) or per cell (protein content). We found that in mitochondria, CI-ATP and CII-ATP were impaired irrespective of the primary LHON mutation and clinical expression. An increase in mitochondrial density per cell compensated for the dysfunctional mitochondria in LHON carriers but was insufficient to result in a normal biochemical phenotype in early-onset LHON patients.al phenotype in early-onset LHON patients.)
Ivarsson 2016 Physiol Behav + (Nitrate supplementation is shown to increa … Nitrate supplementation is shown to increase submaximal force in human and mouse skeletal muscles. In this study, we test the hypothesis that the increased submaximal force induced by nitrate supplementation reduces the effort of submaximal voluntary running, resulting in increased running speed and distance. C57Bl/6N male mice were fed nitrate in the drinking water and housed with or without access to an in-cage running wheel. Nitrate supplementation in sedentary mice had no effect on endurance in a treadmill test, nor did it enhance mitochondrial function. However, after three weeks with in-cage running wheel, mice fed nitrate ran on average 20% faster and 30% further than controls (p<0.01). Compared to running controls, this resulted in ~13% improved endurance on a subsequent treadmill test (p<0.05) and increased mitochondrial oxidative capacity, as judged from a mean increase in citrate synthase activity of 14% (p<0.05). After six weeks with nitrate, the mice were running 58% longer distances per night. When nitrate supplementation was removed from the diet, the running distance and speed decreased to the control level, despite the improved endurance achieved during nitrate supplementation. In conclusion, low-frequency force improvement due to nitrate supplementation facilitates submaximal exercise such as voluntary running.Copyright © 2016 Elsevier Inc. All rights reserved.Copyright © 2016 Elsevier Inc. All rights reserved.)
Larsen 2011 Cell Metab + (Nitrate, an inorganic anion abundant in ve … Nitrate, an inorganic anion abundant in vegetables, is converted in vivo to bioactive nitrogen oxides including NO. We recently demonstrated that dietary nitrate reduces oxygen cost during physical exercise, but the mechanism remains unknown. In a double-blind crossover trial we studied the effects of a dietary intervention with inorganic nitrate on basal mitochondrial function and whole-body oxygen consumption in healthy volunteers. Skeletal muscle mitochondria harvested after nitrate supplementation displayed an improvement in oxidative phosphorylation efficiency (P/O ratio) and a decrease in State 4 respiration with and without atractyloside and respiration without adenylates. The improved mitochondrial P/O ratio correlated to the reduction in oxygen cost during exercise. Mechanistically, nitrate reduced the expression of ATP/ADP translocase, a protein involved in proton conductance. We conclude that dietary nitrate has profound effects on basal mitochondrial function. These findings may have implications for exercise physiology- and lifestyle-related disorders that involve dysfunctional mitochondria.s that involve dysfunctional mitochondria.)
Larsen 2014 Am J Clin Nutr + (Nitrate, which is an inorganic anion abund … Nitrate, which is an inorganic anion abundant in vegetables, increases the efficiency of isolated human mitochondria. Such an effect might be reflected in changes in the resting metabolic rate (RMR) and formation of reactive oxygen species. The bioactivation of nitrate involves its active accumulation in saliva followed by a sequential reduction to nitrite, nitric oxide, and other reactive nitrogen species.We studied effects of inorganic nitrate, in amounts that represented a diet rich in vegetables, on the RMR in healthy volunteers.In a randomized, double-blind, crossover study, we measured the RMR by using indirect calorimetry in 13 healthy volunteers after a 3-d dietary intervention with sodium nitrate (NaNO3) or a placebo (NaCl). The nitrate dose (0.1 mmol ⋅ kg-1 ⋅ d-1) corresponded to the amount in 200-300 g spinach, beetroot, lettuce, or other vegetable that was rich in nitrate. Effects of direct nitrite exposure on cell respiration were studied in cultured human primary myotubes.The RMR was 4.2% lower after nitrate compared with placebo administration, and the change correlated strongly to the degree of nitrate accumulation in saliva (r2 = 0.71). The thyroid hormone status, insulin sensitivity, glucose uptake, plasma concentration of isoprostanes, and total antioxidant capacity were unaffected by nitrate. The administration of nitrite to human primary myotubes acutely inhibited respiration.Dietary inorganic nitrate reduces the RMR. This effect may have implications for the regulation of metabolic function in health and disease. metabolic function in health and disease.)
Boushel 2012 Am J Physiol Regul Integr Comp Physiol + (Nitric oxide (NO) and prostaglandins (PG) … Nitric oxide (NO) and prostaglandins (PG) together play a role in regulation blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome ''c'' oxidase. Indomethacin both uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus inhibition of NO and PG may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG blockade (L-NMMA and indomethacin respectively) on mitochondrial respiration in human muscle following knee extension (KE) exercise. Mitochondrial respiration was measured ''ex-vivo'' by high-resolution respirometry in saponin-permeabilized fibers following 6 min KE in control (CON, ''n''=8), arterial infusion of LNMMA (''n''=4) and Indo (''n''=4) followed by combined inhibition of NO and PG (L-NMMA + Indo, n=8). ADP-stimulated [[State 3]] respiration with substrates for Complex I (glutamate, malate) was reduced 50% by Indo. State 3 O(2) flux with Complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared to CON. The results indicate that indomethacin reduces State 3 mitochondrial respiration primarily at Complex I of the respiratory chain while blockade of NO by addition of L-NMMA counteracts the inhibition of Indo. This metabolic effect in concert with a reduction of blood flow likely accounts for ''in-vivo'' changes in muscle O2 consumption during combined blockade of NO and PG.gt; consumption during combined blockade of NO and PG.)
Uecal 2016 J Neurotrauma + (Nitric oxide (NO) has frequently been asso … Nitric oxide (NO) has frequently been associated with secondary damage after brain injury. However, average NO levels in different brain regions before and after traumatic brain injury (TBI) and its role in post-TBI mitochondrial dysfunction remain unclear. In this comprehensive profiling study, we demonstrate for the first time that basal NO levels vary significantly in the healthy cortex (0.44 ± 0.04 μM), hippocampus (0.26 ± 0.03 μM), and cerebellum (1.24 ± 0.08 μM). Within 4 h of severe lateral fluid percussion injury, NO levels almost doubled in these regions, thereby preserving regional differences in NO levels. TBI-induced NO generation was associated with inducible NO synthase (iNOS) increase in ipsilateral but not in contralateral regions. The transient NO increase resulted in a persistent tyrosine nitration adjacent to the injury site. Nitrosative stress-associated cell loss via apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necrosis were also observed in the ipsilateral cortex, despite high levels of NO in the contralateral cortex. NO-mediated impairment of mitochondrial state 3 respiration dependent on complex I substrates was transient and confined to the ipsilateral cortex. Our results demonstrate that NO dynamics and associated effects differ in various regions of the injured brain. A potential association between the observed mitochondrial electron flow through complex I, but not complex II, and the modulation of TBI induced NO levels in different brain regions has to be prospectively analyzed in more detail. be prospectively analyzed in more detail.)
Aguirre 2010 Biochim Biophys Acta + (Nitric oxide (NO) inhibits mitochondrial r … Nitric oxide (NO) inhibits mitochondrial respiration by decreasing the apparent affinity of cytochrome c oxidase (CIV) for oxygen. Using iNOS-transfected HEK 293 cells to achieve regulated intracellular NO production, we determined NO and O2 concentrations and mitochondrial O2 consumption by high-resolution respirometry over a range of O2 concentrations down to nanomolar. Inhibition of respiration by NO was reversible, and complete NO removal recovered cell respiration above its routine reference values. Respiration was observed even at high NO concentrations, and the dependence of IC50 on [O2] exhibits a characteristic but puzzling parabolic shape; both these features imply that CIV is protected from complete inactivation by NO and are likely to be physiologically relevant. We present a kinetic model of CIV inhibition by NO that efficiently predicts experimentally determined respiration at physiological O2 and NO concentrations and under hypoxia, and accurately predicts the respiratory responses under hyperoxia. The model invokes competitive and uncompetitive inhibition by binding of NO to the reduced and oxidized forms of CIV, respectively, and suggests that dissociation of NO from reduced CIV may involve its O2 dependent oxidation. It also explains the non-linear dependence of IC50 on O2 concentration, and the hyperbolic increase of ''c''50 as a function of NO concentration.sub>50 on O2 concentration, and the hyperbolic increase of ''c''50 as a function of NO concentration.)
Magnifico 2011 Abstract IOC61 + (Nitric oxide (NO) is a biological messenge … Nitric oxide (NO) is a biological messenger which regulates several physiological responses including relaxation of smooth muscle, neurotransmission, inhibition of platelet aggregation, cell migration and mitochondrial respiration. In mammals NO is synthesized by three different gene-encoded NO synthase (NOS), the neuronal NOS (nNOS or NOS1), the inducible NOS (iNOS or NOS2), the endothelial NOS (eNOS or NOS3) and possibly a mitochondrial NOS. Made available exogenously or endogenously, NO reacts with heamoproteins such as guanylate cyclase, haemoglobin, myoglobin and cytochrome c oxidase (CcOX). The NO-CcOX interaction is of particular interest, being rapid and reversible and leading to changes of the ATP synthesis (1). Inhibition may or may not occur in competition with O2, particularly depending on substrates availability (e-, O2) (2). Experimental evidence suggests that NO might be a physiological regulator of cell respiration turning to pathological under circumstances (3-4). Many effectors have been shown to control the enzymatic activity of the NOSs, thus the cell bioavailability of NO. We have focused our attention on the effects of compounds likely involved in the regulation of the level of NO endogenously produced in the cells, such as morphine, melatonin, hydrocortisone (5). Under a number of conditions we have measured the NOSs expression and tentatively correlated the observation to nitrate-nitrite accumulation and parameters of mitochondrial efficiency.[1] Brown GC, Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 356: 295-298.[2] Sarti P et al (2000) Nitric oxide and cytochrome c oxidase: mechanisms of inhibition and NO degradation. Biochim Biophis Res Com 274: 183.[3] Sarti P et al (2003) Nitric oxide and cytochrome oxidase: reaction mechanisms from the enzyme to the cell. Free Radic Biol Med 34: 509-520.[4] Mason MG et al (2006) Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase. Proc Natl Acad Sci U S A 103: 708.[5] Mastronicola D et al (2004) Morphine but not fentanyl and methadone affects mitochondrial membrane potential by inducing nitric oxide release in glioma cells. Cell Mol Life Sci 61: 2991-2997.ma cells. Cell Mol Life Sci 61: 2991-2997.)
Knott 2009 Antioxid Redox Signal + (Nitric oxide (NO) is an important messenge … Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration.ch of the role of NO in neurodegeneration.)
Simonin 2012 Biochem J + (Nitric oxide (NO) is described as an inhib … Nitric oxide (NO) is described as an inhibitor of plant and mammalian respiratory chains due to its high affinity for cytochrome c oxidase (COX), which hinders reduction of oxygen to water. Here we show that in plant mitochondria NO may interfere with other respiratory complexes as well. We analyzed oxygen consumption supported by complex I and/or complex II and/or external NADH dehydrogenase in Percoll-isolated potato tuber (''Solanum tuberosum'') mitochondria. When mitochondrial respiration was stimulated by succinate, adding the NO-donors SNAP or DETA-NONOate caused a 70 % reduction in oxygen consumption rate in state 3 (stimulated with 1 mM of ADP). This inhibition was followed by a significant increase in the KM of succinate dehydrogenase (SDH) for succinate (KM of 0.77 ± 0.19 to 34.3 ± 5.9 mM, in presence of NO). When mitochondrial respiration was stimulated by external NADH dehydrogenase or complex I, NO had no effect on respiration. NO itself and DETA-NONOate had similar effects to SNAP. No significant inhibition of respiration was observed in the absence of ADP. More importantly, SNAP inhibited PTM respiration independently of oxygen tensions, indicating a different kinetic mechanism from that observed in mammalian mitochondria. We also observed, in an FAD reduction assay, that SNAP blocked the intrinsic SDH electron flow in much the same way as thenoyltrifluoroacetone (TTFA), a noncompetitive SDH inhibitor. We suggest that NO inhibits SDH in its ubiquinone site or its Fe-S centers. These data indicate that SDH has an alternative site of NO action in plant mitochondria.e site of NO action in plant mitochondria.)
Dungel 2008 Arch Biochem Biophys + (Nitric oxide (NO) is known to inhibit mito … Nitric oxide (NO) is known to inhibit mitochondrial respiration reversibly. This study aimed at clarifying whether low level illumination at specific wavelengths recovers mitochondrial respiration inhibited by NO and glycerol-trinitrate (GTN), a clinically used NO mimetic. NO fully inhibited respiration of liver mitochondria at concentrations occurring under septic shock. The respiration was completely restored by illumination at the wavelength of 430 nm while longer wavelengths were less effective. GTN inhibited mitochondrial respiration though the efficiency of GTN was lower compared to NO concentrations observed in sepsis models. However, GTN inhibition was absolutely insensitive to illumination regardless of wavelength used. Our data show that visible light of short wavelengths efficiently facilitates the recovery of mitochondria inhibited by NO-gas at the levels generated under septic conditions. The inhibition of mitochondrial respiration by GTN is not sensitive to visible light, suggesting an inhibition mechanism other that NO mediation.ibition mechanism other that NO mediation.)
Patel 1999 Biochim Biophys Acta + (Nitric oxide (NO) plays an important role … Nitric oxide (NO) plays an important role as a cell-signalling molecule, anti-infective agent and, as most recently recognised, an antioxidant. The metabolic fate of NO gives rise to a further series of compounds, collectively known as the reactive nitrogen species (RNS), which possess their own unique characteristics. In this review we discuss this emerging aspect of the NO field in the context of the formation of the RNS and what is known about their effects on biological systems. While much of the insight into the RNS has been gained from the extensive chemical characterisation of these species, to reveal biological consequences this approach must be complemented by direct measures of physiological function. Although we do not know the consequences of many of the dominant chemical reactions of RNS an intriguing aspect is now emerging. This review will illustrate how, when specificity and amplification through cell signalling mechanisms are taken into account, the less significant reactions, in terms of yield or rates, can explain many of the biological responses of exposure of cells or physiological systems to RNS. of cells or physiological systems to RNS.)
Zhan 2018 Mol Cell + (Nitric oxide (NO) regulates diverse cellul … Nitric oxide (NO) regulates diverse cellular signaling through S-nitrosylation of specific Cys residues of target proteins. The intracellular level of S-nitrosoglutathione (GSNO), a major bioactive NO species, is regulated by GSNO reductase (GSNOR), a highly conserved master regulator of NO signaling. However, little is known about how the activity of GSNOR is regulated. Here, we show that S-nitrosylation induces selective autophagy of Arabidopsis GSNOR1 during hypoxia responses. S-nitrosylation of GSNOR1 at Cys-10 induces conformational changes, exposing its AUTOPHAGY-RELATED8 (ATG8)-interacting motif (AIM) accessible by autophagy machinery. Upon binding by ATG8, GSNOR1 is recruited into the autophagosome and degraded in an AIM-dependent manner. Physiologically, the S-nitrosylation-induced selective autophagy of GSNOR1 is relevant to hypoxia responses. Our discovery reveals a unique mechanism by which S-nitrosylation mediates selective autophagy of GSNOR1, thereby establishing a molecular link between NO signaling and autophagy.r link between NO signaling and autophagy.)
De Palma 2014 Skelet Muscle + (Nitric oxide (NO), generated in skeletal m … Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOSμ), has profound effects on both mitochondrial bioenergetics and muscle development and function. The importance of NO for muscle repair emerges from the observation that nNOS signalling is defective in many genetically diverse skeletal muscle diseases in which muscle repair is dysregulated. How the effects of NO/nNOSμ on mitochondria impact on muscle function, however, has not been investigated yet.In this study we have examined the relationship between the NO system, mitochondrial structure/activity and skeletal muscle phenotype/growth/functions using a mouse model in which nNOSμ is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells.We show that nNOSμ deficiency in mouse skeletal muscle leads to altered mitochondrial bioenergetics and network remodelling, and increased mitochondrial unfolded protein response (UPR(mt)) and autophagy. The absence of nNOSμ is also accompanied by an altered mitochondrial homeostasis in myogenic precursor cells with a decrease in the number of myonuclei per fibre and impaired muscle development at early stages of perinatal growth. No alterations were observed, however, in the overall resting muscle structure, apart from a reduced specific muscle mass and cross sectional areas of the myofibres. Investigating the molecular mechanisms we found that nNOSμ deficiency was associated with an inhibition of the Akt-mammalian target of rapamycin pathway. Concomitantly, the Akt-FoxO3-mitochondrial E3 ubiquitin protein ligase 1 (Mul-1) axis was also dysregulated. In particular, inhibition of nNOS/NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent-protein kinases induced the transcriptional activity of FoxO3 and increased Mul-1 expression. nNOSμ deficiency was also accompanied by functional changes in muscle with reduced muscle force, decreased resistance to fatigue and increased degeneration/damage post-exercise.Our results indicate that nNOSμ/NO is required to regulate key homeostatic mechanisms in skeletal muscle, namely mitochondrial bioenergetics and network remodelling, UPR(mt) and autophagy. These events are likely associated with nNOSμ-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance.ulting in a deficit of muscle performance.)
Dias 2022 Free Radic Biol Med + (Nitrite has been viewed in the past essent … Nitrite has been viewed in the past essentially as an inert metabolic endpoint of nitric oxide (•NO). However, it has become evident that, under certain conditions, nitrite can be a source of •NO. In the brain, this alternative source of •NO production independent of nitric oxide synthase activity may be particularly relevant in ischemia/reperfusion (I/R), where low oxygen availability limits enzymatic production of •NO. Notably, ''in vivo'' concentration of nitrite can be easily increased with diet, through the ingestion of nitrate-rich foods, opening the window for a therapeutic intervention based on diet. Considering the modulation of mitochondrial respiration by •NO, we have hypothesized that the protective action of nitrite in I/R may also result from modulation of mitochondrial function. We used high-resolution respirometry to evaluate the effects of nitrite in two ''in vitro'' models of I/R. In both cases, an increase in oxygen flux was observed following reoxygenation, a phenomenon that has been coined "oxidative burst". The amplitude of this "oxidative burst" was decreased by nitrite in a concentration-dependent manner. Additionally, a pilot ''in vivo'' study in which animals received a nitrate-rich diet as a strategy to increase circulating and tissue levels of nitrite also revealed that the "oxidative burst" was decreased in the nitrate-treated animals. These results may provide mechanistic support to the observation of a protective effect of nitrite in situations of brain ischemia.hanistic support to the observation of a protective effect of nitrite in situations of brain ischemia.)
Bundgaard 2016 Abstract IOC115 + (Nitrite protects the heart from toxic oxyg … Nitrite protects the heart from toxic oxygen radicals when oxygen returns after a period of oxygen deprivation, such as after heart attack or infarct. During anoxia, nitrite can inhibit inactive proteins, such as complex I in the electron transport chain, by a post-translational modification termed S-nitrosation, where an NO-moiety binds protein cysteines. Inhibition of complex I have been shown to limit the production of oxygen radicals, thereby protecting the heart from oxidative damage [1]. Some extreme animals, such as the red-eared slider turtle, survive the winter at the bottom of frozen ponds, and remain completely deprived of oxygen for several months. Unlike mammals, these turtles are not maimed by reoxygenation, but wake up in the spring with healthy hearts. Nitrite is naturally accumulated in the hearts of these animals during anoxia, which might protect them from reperfusion damage [2]. In this study, we investigate the protective effects of nitrite on the turtle heart. ''In vitro'' studies on isolated mitochondria have shown that the artificial S-nitrosating agent MitoSNO S-nitrosates turtle complex I which decreases activity of the enzyme and reduces ROS production upon reoxygenation, but does not affect respiration rate. Further, we have shown that succinate is accumulated in the anoxic turtle heart, which has been shown in mice to fuel the ROS production that occurs upon reoxygenation. This would corroborate the need for inhibition of complex I in the turtle.We further wish to investigate whether the accumulated nitrite in the anoxic turtle mimics the protective effect of S-nitrosation ''in vitro'' and whether this is involved in keeping the turtle heart healthy upon awakening in the spring after a long, oxygen-deprived winter. Using extreme animals such as the turtle as models for coping with extreme situations like oxygen deprivation might teach us how to protect the more sensitive human heart.to protect the more sensitive human heart.)
Dungel 2015 Free Radic Biol Med + (Nitrite protects various organs from ische … Nitrite protects various organs from ischemia-reperfusion injury by ameliorating mitochondrial dysfunction. Here we provide evidence that this protection is due to the inhibition of iron-mediated oxidative reactions caused by the release of iron ions upon hypoxia. We show in a model of isolated rat liver mitochondria that upon hypoxia, mitochondria reduce nitrite to nitric oxide (NO) in amounts sufficient to inactivate redox-active iron ions by formation of inactive dinitrosyl iron complexes (DNIC). The scavenging of iron ions in turn prevents the oxidative modification of the outer mitochondrial membrane and the release of cytochrome c during reoxygenation. This action of nitrite protects mitochondrial function. The formation of DNIC with nitrite-derived NO could also be confirmed in an ischemia-reperfusion model in liver tissue. Our data suggest that the formation of DNIC is a key mechanism of nitrite-mediated cytoprotection.hanism of nitrite-mediated cytoprotection.)
Sanchez-Calvo 2016 PLOS ONE + (Nitro-arachidonic acid (NO2-AA) is a cell … Nitro-arachidonic acid (NO2-AA) is a cell signaling nitroalkene that exerts anti-inflammatory activities during macrophage activation. While angiotensin II (ANG II) produces an increase in reactive oxygen species (ROS) production and mitochondrial dysfunction in renal tubular cells, little is known regarding the potential protective effects of NO2-AA in ANG II-mediated kidney injury. As such, this study examines the impact of NO2-AA on ANG II-induced mitochondrial dysfunction in an immortalized renal proximal tubule cell line (HK-2 cells). Treatment of HK-2 cells with ANG II increases the production of superoxide (O2●-), nitric oxide (●NO), inducible nitric oxide synthase (NOS2) expression, peroxynitrite (ONOO-) and mitochondrial dysfunction. Using high-resolution respirometry, it was observed that the presence of NO2-AA prevented ANG II-mediated mitochondrial dysfunction. Attempting to address mechanism, we treated isolated rat kidney mitochondria with ONOO-, a key mediator of ANG II-induced mitochondrial damage, in the presence or absence of NO2-AA. Whereas the activity of succinate dehydrogenase (SDH) and ATP synthase (ATPase) were diminished upon exposure to ONOO-, they were restored by pre-incubating the mitochondria with NO2-AA. Moreover, NO2-AA prevents oxidation and nitration of mitochondrial proteins. Combined, these data demonstrate that ANG II-mediated oxidative damage and mitochondrial dysfunction is abrogated by NO2-AA, identifying this compound as a promising pharmacological tool to prevent ANG II-induced renal disease.l to prevent ANG II-induced renal disease.)
Kuehn 2018 Biochem Pharmacol + (Nitro-fatty acids (NFAs) are endogenously … Nitro-fatty acids (NFAs) are endogenously occurring lipid mediators exerting strong anti-inflammatory effects and acting as anti-oxidants in a number of animal models of inflammation. These NFA effects are mediated by targeting important regulatory proteins involved in inflammatory processes, such as 5-lipoxygenase, soluble epoxide hydrolase, or NF-κB. In the present study, we investigated the anti-tumorigenic effects of NFAs on colorectal cancer (CRC) cells in cell culture-based experiments and in a murine xenograft model of human CRC. We could show that 9-NOA suppresses the viability of CRC cells (HCT-116 and HT-29) by inducing a caspase-dependent apoptosis via the intrinsic apoptotic pathway. Co-treatment with the pan-caspase inhibitor Q-VD-OPH counteracted the NFA-mediated apoptosis in both cell lines. Furthermore, NFAs affected the cell cycle transition and reduced the oxygen consumption rate (OCR) immediately. On the contrary to their well-known anti-oxidative properties, NFAs mediated the generation of mitochondrial oxidative stress in human CRC cells. Additionally, similar to the cytostatic drug mitomycin, 9-NOA significantly reduced tumor growth in a murine xenograft model of human colorectal cancer. In contrast to the established cytostatic drug, 9-NOA treatment was well tolerated by mice. This study delivers a novel mechanistic approach for nitro-fatty acid-induced inhibition of CRC cell growth by targeting mitochondrial functions such as the mitochondrial membrane potential and mitochondrial respiration. We suggest these naturally occurring lipid mediators as a new class of well tolerated chemotherapeutic drug candidates for treatment of CRC or potentially other inflammation-driven cancer types.ly other inflammation-driven cancer types.)
Bosworth 2009 Proc Natl Acad Sci U S A + (Nitrosothiols (RSNO), formed from thiols a … Nitrosothiols (RSNO), formed from thiols and metabolites of nitric oxide (•NO), have been implicated in a diverse set of physiological and pathophysiological processes, although the exact mechanisms by which they are formed biologically are unknown. Several candidate nitrosative pathways involve the reaction of •NO with O2, reactive oxygen species (ROS), and transition metals. We developed a strategy using extracellular ferrocyanide to determine that under our conditions intracellular protein RSNO formation occurs from reaction of •NO inside the cell, as opposed to cellular entry of nitrosative reactants from the extracellular compartment. Using this method we found that in RAW 264.7 cells RSNO formation occurs only at very low (<8 μM) O2 concentrations and exhibits zero-order dependence on •NO concentration. Indeed, RSNO formation is not inhibited even at O2 levels <1 μM. Additionally, chelation of intracellular chelatable iron pool (CIP) reduces RSNO formation by >50%. One possible metal-dependent, O2-independent nitrosative pathway is the reaction of thiols with dinitrosyliron complexes (DNIC), which are formed in cells from the reaction of •NO with the CIP. Under our conditions, DNIC formation, like RSNO formation, is inhibited by ≈50% after chelation of labile iron. Both DNIC and RSNO are also increased during overproduction of ROS by the redox cycler 5,8-dimethoxy-1,4-naphthoquinone. Taken together, these data strongly suggest that cellular RSNO are formed from free •NO via transnitrosation from DNIC derived from the CIP. We have examined in detail the kinetics and mechanism of RSNO formation inside cells.from the CIP. We have examined in detail the kinetics and mechanism of RSNO formation inside cells.)

Wieland 1922 Ergeb Physiol Biol Chem Exp Pharmakol + (No Abstract)

Klingenberg 1960 Biochem Z + (No Abstract [Article in German])
Fowler 1962 Biochim Biophys Acta + (No Abstract supplied.)
Kuboyama 1962 Biochem Biophys Res Commun-IX + (No Abstract supplied.)
Klingenberg 1961 Biochem Z-II + (No Abstract supplied.)
Klingenberg 1963 Biochem Z + (No Abstract supplied.)
Rossi 1963 Biochem Z + (No Abstract supplied.)
Danielson 1963 Biochem Z + (No Abstract supplied.)
Lee 1964 Biochim Biophys Acta + (No Abstract supplied.)
Lee 1964 Nature + (No Abstract supplied.)
Moore 1964 Biochem Biophys Res Commun + (No Abstract supplied.)
O-Uchi 2012 J Gen Physiol + (No abstract available)
Zweck 2021 Diabetes Care + (No abstract available)
Mitchell 1975 FEBS Letters + (No abstract available.)
Luft 1962 J Clin Invest + (No abstract available.)
Gudkov 2010 Dokl Biochem Biophys + (No abstract provided. Please follow PubMed-Link above.)
Klingenberg 1961 Biochem Z-III + (No abstract supplied.)
Ernster 1962 Nature + (No abstract supplied.)
Brierley 1962 Proc Natl Acad Sci USA + (No abstract supplied.)
Wollenberger 1961 J Biophys Biochem Cytol + (No abstract supplied.)
Aoun 2012 J Bioenerg Biomembr + (No data are reported on changes in mitocho … No data are reported on changes in mitochondrial membrane phospholipids in non-alcoholic fatty liver disease. We determined the content of mitochondrial membrane phospholipids from rats with non alcoholic liver steatosis, with a particular attention for cardiolipin (CL) content and its fatty acid composition, and their relation with the activity of the mitochondrial respiratory chain complexes. Different dietary fatty acid patterns leading to steatosis were explored. With high-fat diet, moderate macrosteatosis was observed and the liver mitochondrial phospholipid class distribution and CL fatty acids composition were modified. Indeed, both CL content and its C18:2n-6 content were increased with liver steatosis. Moreover, mitochondrial ATP synthase activity was positively correlated to the total CL content in liver phospholipid and to CL C18:2n-6 content while other complexes activity were negatively correlated to total CL content and/or CL C18:2n-6 content of liver mitochondria. The lard-rich diet increased liver CL synthase gene expression while the fish oil-rich diet increased the (n-3) polyunsaturated fatty acids content in CL. Thus, the diet may be a significant determinant of both the phospholipid class content and the fatty acid composition of liver mitochondrial membrane, and the activities of some of the respiratory chain complex enzymes may be influenced by dietary lipid amount in particular via modification of the CL content and fatty acid composition in phospholipid.nd fatty acid composition in phospholipid.)
Giulivi 2008 Biochem J + (No studies have been performed on the mito … No studies have been performed on the mitochondria of malaria vector mosquitoes. This information would be valuable in understanding mosquito aging and detoxification of insecticides, two parameters that have a significant impact on malaria parasite transmission in endemic regions. In the present study, we report the analyses of respiration and oxidative phosphorylation in mitochondria of cultured cells [ASE (Anopheles stephensi Mos. 43) cell line] from A. stephensi, a major vector of malaria in India, South-East Asia and parts of the Middle East. ASE cell mitochondria share many features in common with mammalian muscle mitochondria, despite the fact that these cells are of larval origin. However, two major differences with mammalian mitochondria were apparent. One, the glycerol-phosphate shuttle plays as major a role in NADH oxidation in ASE cell mitochondria as it does in insect muscle mitochondria. In contrast, mammalian white muscle mitochondria depend primarily on lactate dehydrogenase, whereas red muscle mitochondria depend on the malate-oxaloacetate shuttle. Two, ASE mitochondria were able to oxidize proline at a rate comparable with that of alpha-glycerophosphate. However, the proline pathway appeared to differ from the currently accepted pathway, in that oxoglutarate could be catabolized completely by the tricarboxylic acid cycle or via transamination, depending on the ATP need.transamination, depending on the ATP need.)
Christiansen 2015 J Vet Med Sci + (No studies have investigated the mitochond … No studies have investigated the mitochondrial function in permeabilized muscle fiber from cats. The aim of this study was to investigate tissue-specific and substrate-specific characteristics of mitochondrial oxidative phosphorylation (OXPHOS) capacity in feline permeabilized oxidative muscle fibers. Biopsies of left ventricular cardiac muscle and soleus muscle, a type I-rich oxidative skeletal muscle, were obtained from 15 healthy domestic cats. Enzymatic activity of citrate synthase (CS), a biomarker of mitochondrial content, was measured. Mitochondrial OXPHOS capacity with various kinds of non-fatty-acid substrates and fatty-acid substrate in permeabilized muscle fiber was measured by using high-resolution respirometry. CS activity in the heart was 3 times higher than in the soleus muscle. Mitochondrial state 3 respiration, ADP-stimulated respiration, with complex I-linked and complex I+II-linked substrates, respectively, was significantly higher in the heart than in the soleus muscle when normalized for muscle mass, but not for CS activity, indicating that greater capacity for mitochondrial OXPHOS with these non-fatty-acid substrates in the heart may depend on higher mitochondrial content. In contrast, the soleus muscle had higher mitochondrial state 3 respiration with fatty acids than the heart when normalized for CS activity, indicating greater capacity for fatty-acid oxidation per mitochondrion in the soleus. Our findings suggest that there are tissue- specific and substrate-specific quantitative and qualitative differences in mitochondrial OXPHOS capacity between the different types of oxidative muscles from cats.rent types of oxidative muscles from cats.)
Morales-Rubio 2023 Sci Rep + (Noise is present in cell biology. The capa … Noise is present in cell biology. The capability of cells to respond to noisy environment have become essential. This study aimed to investigate whether noise can enhance the contractile response and Ca2+ handling in cardiomyocytes from a cardiomyopathy model. Experiments were conducted in an experimental setup with Gaussian white noise, frequency, and amplitude control to stimulate myocytes. Cell shortening, maximal shortening velocity, time to peak shortening, and time to half relaxation variables were recorded to cell shortening. Ca2+ transient amplitude and raise rate variables were registered to measure Ca2+ transients. Our results for cell shortening, Ca2+ transient amplitude, and raise rate suggest that cell response improve when myocytes are noise stimulated. Also, cell shortening, maximal shortening velocity, Ca2+ transient amplitude, and raise improves in control cells. Altogether, these findings suggest novel characteristics in how cells improve their response in a noisy environment.ese findings suggest novel characteristics in how cells improve their response in a noisy environment.)
Jelenik 2014 Diabetologie und Stoffwechsel + (Non-alcoholic fatty liver (NAFL) and insul … Non-alcoholic fatty liver (NAFL) and insulin resistance increase the risk of cardiac mortality and associate with impaired muscular and hepatic mitochondrial function. We hypothesized that also cardiac energy metabolism is altered in mice with insulin resistance and NAFL.Mice with adipose tissue-specific overexpression of the sterol regulatory-element binding protein-1c, which have lipodystrophy and develop NAFL (NAFL), and wild-type controls (CON), underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (IS, ''n'' = 5 – 7). Systolic blood pressure was measured with catheters introduced into the left ventricle. Mitochondrial respiration and H2O2 production from cardiac mitochondria were assessed by high-resolution respirometry and the Amplex Red method, respectively (''n'' = 7).Peripheral and hepatic IS were lower in NAFL mice compared to CON (-71% and -70%; ''p'' < 0.05). Accordingly, NAFL mice were hyperglycemic (216 ± 36 vs. 108 ± 14 mg/dl, ''p'' < 0.05), hyperinsulinemic (76 ± 17 vs. 12 ± 5µU/ml, ''p'' < 0.05) and dyslipidemic (fatty acids: 1.17 ± 0.2 vs. 0.73 ± 0.44 mmol/l, ''p'' < 0.05). Heart to body weight ratio was increased by 34%, while blood pressure was unchanged. Glycolysis- and β-oxidation-derived mitochondrial oxidative capacity was increased by 93% (2.86 ± 0.06, CON: 1.47 ± 0.43 nmol/mg protein/s; ''p'' < 0.05) and by 125% (2.45 ± 0.66, CON: 1.09 ± 0.22 nmol/mg protein/s; ''p'' < 0.05) in the heart of NAFL mice, respectively. H2O2 production by mitochondrial complex III was 51% higher (''p'' < 0.05), compared to age-matched CON.Insulin resistance in mice with hepatic steatosis associates with non-hypertensive cardiac hypertrophy and increased energy demand of heart. Accumulation of oxidative stress, as a result of increased mitochondrial respiration, could render hearts vulnerable for ischemic intolerance and impaired myocardial function.able for ischemic intolerance and impaired myocardial function.)
Cho 2022 BMC Med + (Non-alcoholic fatty liver disease (NAFLD) … Non-alcoholic fatty liver disease (NAFLD) can lead to pulmonary dysfunction that is associated with pulmonary inflammation. Moreover, little is known regarding the therapeutic role of exercise training on pulmonary pathophysiology in NAFLD. The present study aimed to investigate the effect of exercise training on high-fat high-carbohydrate (HFHC)-induced pulmonary dysfunction in C57BL/6 mice.Male C57BL/6 mice (N = 40) were fed a standard Chow (n = 20) or an HFHC (n = 20) diet for 15 weeks. After 8 weeks of dietary treatment, they were further assigned to 4 subgroups for the remaining 7 weeks: Chow (n = 10), Chow plus exercise (Chow+EX, n = 10), HFHC (n = 10), or HFHC plus exercise (HFHC+EX, n = 10). Both Chow+EX and HFHC+EX mice were subjected to treadmill running.Chronic exposure to the HFHC diet resulted in obesity with hepatic steatosis, impaired glucose tolerance, and elevated liver enzymes. The HFHC significantly increased fibrotic area (p < 0.001), increased the mRNA expression of TNF-α (4.1-fold, p < 0.001), IL-1β (5.0-fold, p < 0.001), col1a1 (8.1-fold, p < 0.001), and Timp1 (6.0-fold, p < 0.001) in the lung tissue. In addition, the HFHC significantly altered mitochondrial function (p < 0.05) along with decreased Mfn1 protein levels (1.8-fold, p < 0.01) and increased Fis1 protein levels (1.9-fold, p < 0.001). However, aerobic exercise training significantly attenuated these pathophysiologies in the lungs in terms of ameliorating inflammatory and fibrogenic effects by enhancing mitochondrial function in lung tissue (p < 0.001).The current findings suggest that exercise training has a beneficial effect against pulmonary abnormalities in HFHC-induced NAFLD through improved mitochondrial function.lities in HFHC-induced NAFLD through improved mitochondrial function.)