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Sulfide catabolism ameliorates hypoxic brain injury | Nature Communications
What Makes a Neuron Fire? 17 Spike-Train Statistics 24 The Neural Code 34 Chapter Summary 39 Appendices 40 Annotated Bibliography 43 2 Neural Encoding II: Reverse Correlation and Visual Receptive Fields 45 Introduction 45 Estimating Firing Rates 45 Introduction to the Early Visual System 51 Jan 07, · On the cover: Viruses pose a constant threat to human health. In this issue, Hoffmann et al. (–) and Schneider et al. (–) determine that the transmembrane protein TMEM41B is required for infection by members of the Flaviviridae and Coronaviridae virus families Jun 02, · Vascular contributions to cognitive impairment and dementia (VCID) are conditions arising from vascular diseases or abnormalities that result in cognitive impairments. Unfortunately, the pathophysiology of VCID remains to be elucidated. Now, Qiu et al. used samples from patients with vascular dementia and mouse models to show that cis P-tau was increased in the brain and played a
From neuron to brain nicholls pdf download
Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date from neuron to brain nicholls pdf download or turn off compatibility mode in Internet Explorer.
In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase SQOR and the capacity to catabolize sulfide.
Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver.
Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.
The mechanisms underlying the sensitivity of the brain to hypoxia are incompletely understood. During aerobic respiration, adenosine triphosphate ATP is predominantly produced by oxidative phosphorylation using the electrochemical gradient produced via the mitochondrial electron transfer chain ETC.
Molecular oxygen serves as the terminal electron acceptor that binds and accepts electrons from cytochrome c oxidase COX, complex IVthe last enzyme in the ETC.
Persistent lack of oxygen beyond a few minutes irreversibly damages neurons. Paradoxically, the re-introduction of oxygen contributes to further injury 8. Cytochrome c oxidase has a high affinity for oxygen with a K m of 0, from neuron to brain nicholls pdf download. This apparent gap between the critical brain tissue PO 2 level and the K m of COX suggests that there is a role for additional factors that contribute to the inhibition of ETC under hypoxic conditions.
In addition to oxygen shortage, several gases including hydrogen sulfide H 2 Snitric oxide NOand carbon from neuron to brain nicholls pdf download inhibit mitochondrial respiration 9.
H 2 S is generally considered a highly toxic substance for aerobic organisms as it inhibits COX 10 However, H 2 S also has a number of physiological functions Sulfides are catabolized in mitochondria by sulfide oxidation enzymes. The oxidation of sulfide to persulfide, catalyzed by SQOR, is considered to be the first and rate-limiting step in sulfide oxidation Persulfide is further oxidized to thiosulfate, sulfite, and sulfate by persulfide dioxygenase SDO or ETHE1thiosulfate sulfurtransferase TSTand sulfite oxidase SUOX.
Because the brain of these animals has limited capacity to catabolize sulfide 17the brain is particularly sensitive to the adverse effects of sulfide accumulation.
For example, loss of ETHE1 causes fatal sulfide toxicity in ethylmalonic encephalopathy In addition, the deficiency of SQOR was recently reported to cause Leigh syndrome-like disease characterized by encephalopathy and the presence of brain lesions in the basal ganglia and cortex These observations suggest a critical role of sulfide catabolism in normal cerebral energy homeostasis.
However, the effects of sulfide catabolism on brain bioenergetics during acute oxygen deprivation have thus far attracted little attention. Under physiological conditions, sulfide oxidation by SQOR donates electrons to mitochondrial ETC complex III via coenzyme Q CoQthereby potentially promoting ATP synthesis 2021 In addition, it has been suggested that persulfide produced by From neuron to brain nicholls pdf download sulfide oxidation may serve as an electron acceptor from ETC, facilitating mitochondrial ATP production 15 However, from neuron to brain nicholls pdf download, hypoxia increases the production of sulfide while inhibiting its oxidation, from neuron to brain nicholls pdf download, leading to sulfide accumulation 2425 Hypoxia also impedes persulfide oxidation by ETHE1 as this reaction requires oxygen Excess sulfide promotes the production of NO and reactive oxygen species ROS 272829which, together with sulfide, impair oxidative phosphorylation during ischemia from neuron to brain nicholls pdf download increase reperfusion injury Therefore, from neuron to brain nicholls pdf download, sulfide catabolism may play a pivotal role in cerebral energy homeostasis during acute oxygen shortage and in subsequent brain injury upon reoxygenation, from neuron to brain nicholls pdf download.
In this study, while examining the effects of chronic intermittent H 2 S breathing in mice, we unexpectedly discovered that upregulation of the capacity to catabolize sulfide makes mice remarkably resistant to otherwise lethal hypoxia. Based on this serendipitous discovery, we sought to elucidate the role of sulfide metabolism in the sensitivity of the mammalian brain to hypoxia. We report that increased sulfide oxidation by SQOR makes brains resistant to hypoxia or cerebral ischemia.
We also show that pharmacologically scavenging sulfide, so as to avoid sulfide accumulation in the brain, maintains mitochondrial energy production during oxygen shortage and prevents ischemic or hypoxic brain injury. Our study uncovers the critical role of sulfide catabolism in mitochondrial energy homeostasis during hypoxia and lays a foundation for a novel approach to the treatment of ischemic or hypoxic brain injury.
Breathing H 2 S depresses metabolism and decreases the body temperature of rodents 31 However, as we previously showed, intermittent breathing of H 2 S for 5 days makes male wild-type mice tolerant to the hypo-metabolic effects of inhaled H 2 S Fig. Because chronic sulfide exposure might induce enzymes that increase the capacity to metabolize sulfide, we examined the impact of intermittent H 2 S breathing for 5 days sulfide pre-conditioning, SPC on sulfide metabolism.
Mice were studied 24 h after the last H 2 S exposure on the 6th daywhen the metabolism and body temperature of the mice had completely recovered Supplementary Fig. When control not sulfide pre-conditioned mice acutely breathed H 2 S, from neuron to brain nicholls pdf download, there was a decrease in whole-body metabolism, as measured by a decreased rate of CO 2 production VCO 2 Fig.
In contrast, in mice that were pre-conditioned with H 2 S, subsequent acute H 2 S exposure had no effect on VCO 2. Breathing H 2 S increased plasma levels of sulfide and thiosulfate to a similar extent in control and sulfide pre-conditioned mice From neuron to brain nicholls pdf download. However, breathing H 2 S increased the levels of sulfide and thiosulfate only in the brains of control mice, but not in the brains of sulfide pre-conditioned mice Fig.
Thus, sulfide pre-conditioning may induce tolerance to the inhibitory effects of H 2 S on metabolism by upregulating sulfide catabolism in the brain.
a Body temperature of control and sulfide pre-conditioned SPC mice. b Whole-body CO 2 production rate VCO 2 of SPC and control mice during H 2 S breathing on the 6th day after starting SPC or control air breathing. Data are presented as mean ± SEM or mean and individual values. Survival rates were estimated using the Kaplan—Meier method and a log-rank test was used to compare the survival curves between groups in g.
A two-tailed unpaired t -test was performed for m — o. To investigate the mechanisms responsible for the inhibition of sulfide accumulation during hypoxia in mice pre-conditioned with H 2 S, we measured the levels of enzymes that synthesize or catabolize sulfide. Acquired tolerance to acute hypoxia in sulfide pre-conditioned mice was associated with increased levels of SQOR in the brain, but not in the heart presumably due to higher baseline SQOR levels in the heart than in the brain Fig.
Increments of brain SQOR levels by sulfide pre-conditioning temporarily coincided with the acquisition of hypoxia tolerance; sulfide pre-conditioning for 5 days, but not 2 days, induced hypoxia tolerance and increased brain SQOR levels Supplementary Fig. Levels of other enzymes that metabolize sulfide were not affected by sulfide pre-conditioning in either brain or from neuron to brain nicholls pdf download heart Supplementary Fig.
Because sulfide pre-conditioning increased SQOR levels in the brain, we posited that sulfide pre-conditioning upregulates the ability of brain mitochondria to catabolize sulfide and thereby prevents sulfide-induced from neuron to brain nicholls pdf download of oxidative phosphorylation.
Sulfide pre-conditioning did not affect baseline ATP turnover in isolated brain mitochondria as determined by measuring oxygen consumption rates OCR. In control mice, incubation with Na 2 S a sulfide donor, that mimics hypoxia dose-dependently decreased ATP turnover in isolated mitochondria obtained from the brain, but not liver that has high basal levels of SQOR Fig.
In contrast, the ability of Na 2 S to depress ATP turnover in the brain mitochondria of sulfide pre-conditioned mice was attenuated Fig. Although previous studies suggested that chronic exposure to H 2 S increases mitochondrial biogenesis 34sulfide pre-conditioning did not affect the levels of mitochondrial DNA in the brain or heart of treated mice Supplementary Fig. Chronic exposure to hypoxia is known to increase red blood cell mass and the oxygen affinity of hemoglobin However, five days of sulfide pre-conditioning did not affect either hemoglobin levels or the oxygen dissociation curve of murine red blood cells.
Hydrogen sulfide was previously shown to upregulate hypoxia-inducible factor-1α HIF-1α and one of its canonical targets vascular endothelial growth factor VEGF in vascular endothelial cells and to activate HIF-1α in C. elegans 36 Taken together, these observations suggest that sulfide pre-conditioning confers tolerance to hypoxia via upregulation of SQOR and sulfide catabolism, from neuron to brain nicholls pdf download, rather than as a result of increased mitochondrial biogenesis, increased oxygen delivery by hemoglobin, or upregulation of canonical HIF-1α targets.
Compared to the brains of 8-week old male CD-1 mice, the brains of age-matched female CD-1 mice have ~3-fold and ~1. To investigate the effects of SQOR levels on the ability of the murine brain to tolerate acute oxygen shortage, we subjected CD-1 mice to hypoxia using environmental chambers.
Of note, higher SQOR levels in the brain of female mice appear to be estrogen-dependent. Ovariectomy decreased mRNA and protein levels of SQOR in the brain and abolished hypoxia tolerance in female mice, whereas estrogen supplementation restored brain SQOR mRNA levels and hypoxia tolerance and tended to restore SQOR protein levels in ovariectomized female mice Fig. Vin, vinculin. Impact of sulfide Na 2 S on ADP-induced changes in NADH levels, mitochondrial membrane potential TMRM, tetramethylrhodamine methylesterand oxygen consumption rates OCR in suspensions of isolated brain mitochondria from g male and h female WT mice.
Representative traces of three independent experiments in each genotype. j Structure of AAV containing shRNA against mouse SQOR AAV-shSQOR under a U6 promoter for RNA polymerase III and control AAV AAV-Ctrl. ITR, inverted terminal repeat, EGFP, enhanced green fluorescent protein, CMV, cytomegalovirus, bGH, from neuron to brain nicholls pdf download, bovine growth hormone.
kl Representative immunofluorescence images of the brain sections of CD-1 mice stained with from neuron to brain nicholls pdf download anti-GFP antibody 8 weeks after injection of AAV-Ctrl into ICV.
From neuron to brain nicholls pdf download in l shows a blow-up of a part of the image in k enclosed in a red box. A two-tailed unpaired t -test was performed for aband m. Survival rates were estimated using the Kaplan—Meier method and a log-rank test was used to compare the survival curves between groups in cfand n. To investigate the role of SQOR in sulfide catabolism and mitochondrial respiration, we examined the impact of exogenous sulfide, which mimics hypoxia, on mitochondrial respiration in suspensions of brain mitochondria isolated from male and female mice.
We used a custom-made spectrophotometer 38 to simultaneously measure the ADP-induced changes in NADH levels, mitochondrial membrane potential ΔΨm, measured with tetramethylrhodamine, methylester, TMRMand OCR before and after addition of Na 2 S.
In both male and female mice, in the presence of pyruvate and malate 2. These observations suggest that higher levels of SQOR in female brain mitochondria confer resistance to hypoxia-induced sulfide accumulation and inhibition of mitochondrial respiration.
To further investigate whether increased brain SQOR levels are responsible for the relative resistance of female mice to hypoxia, we used shRNA targeting mouse Sqor shSQOR to knock down SQOR. Adeno-associated virus vectors AAV-shSQOR or control AAV-Ctrl were administered at 10 10 viral particles per cerebral hemisphere to newborn female CD-1 mice on postnatal day 0 P0via intracerebroventricular ICV injection, as described previously Fig. Eight weeks after administration of the AAV, we observed widespread GFP expression in neurons throughout the brain Fig.
Levels of SQOR mRNA, but none of the other enzymes in the transsulfuration and sulfide oxidation pathways, were significantly decreased throughout the brain of mice infected with AAV-shSQOR Fig. These results support the hypothesis that the higher levels of SQOR in the brains of female mice resulted in a greater capacity to oxidize sulfide and contribute to a greater tolerance to hypoxia.
To elucidate the role of SQOR in mitochondrial bioenergetics during oxygen deprivation, we developed mice that lack SQOR in mitochondria. By using CRISPR-Cas9 technology, we disrupted the translation start codon ATG of the murine Sqor gene via a bp deletion Fig.
a Schematic illustration of the murine Sqor gene structure and sequences of WT and mutant alleles spanning the translation initiation codon. Blue letters and black letters indicate the first intron and the second exon, respectively. ATG enclosed by a box indicates the first methionine codon. A target sequence of gRNA is underlined. Target sequences for genotyping primers are indicated by arrows.
b PCR detection of a deletion in the Sqor gene. Representative PCR gel images of 3 independent biological replicates of each are shown. Representative immunoblots of 3 independent biological replicates for each are shown.
Solving the Brain: Pioneering Tomorrow's Neurotechnologies
, time: 59:07From neuron to brain nicholls pdf download
Jun 02, · Patients with COVID can develop loss of smell and/or taste. Unfortunately, the pathophysiology of these alterations remains unclear. Here, de Melo et al. examined the olfactory mucosa in patients with COVID reporting loss of smell and detected SARS-CoV-2 viral particles and inflammation in multiple cell types in the olfactory neuroepithelium, including olfactory sensory neurons Apr 15, · A letter by Oud et al. () raised an issue on the authenticity of the PIWIL1 D-box mutations we identified in 3 out of Han Chinese patients with idiopathic azoospermia (Gou et al., ). By sequencing a cohort of infertile men from Europe, the United States, and Australia, these authors could not detect the identical mutations in PIWIL1 as we reported in the patients of Han Jan 07, · On the cover: Viruses pose a constant threat to human health. In this issue, Hoffmann et al. (–) and Schneider et al. (–) determine that the transmembrane protein TMEM41B is required for infection by members of the Flaviviridae and Coronaviridae virus families
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