The Response of <i>Caenorhabditis elegans</i> to Hydrogen Sulfide and Hydrogen Cyanide

Budde, Mark W.; Roth, Mark B.

doi:10.1534/genetics.111.129841

Cited by 76 publications

(118 citation statements)

References 46 publications

(67 reference statements)

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“…1, C and D). The tm3378 allele of sqrd-1 is a 445 bp deletion that removes exon two and is a predicted molecular null (13). We confirmed the previous observation that sqrd-1(tm3378) mutant animals die when exposed to H 2 S (13), though we found that it takes at least 10 h before sqrd-1(tm3378) mutant animals succumb in 50 ppm H 2 S. For this reason, we only measured translation for up to three hours of H 2 S exposure, at which time sqrd-1(tm3378) animals were mobile and visibly indistinguishable from untreated animals and wild-type controls.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Horsman¹,

Miller

2016

Journal of Biological Chemistry

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Hydrogen sulfide (H 2 S) is an endogenously produced gaseous molecule with important roles in cellular signaling. In mammals, exogenous H 2 S improves survival of ischemia/reperfusion. We have previously shown that exposure to H 2 S increases the lifespan and thermotolerance in Caenorhabditis elegans, and improves protein homeostasis in low oxygen. The mitochondrial SQRD-1 (sulfide quinone oxidoreductase) protein is a highly conserved enzyme involved in H 2 S metabolism. SQRD-1 is generally considered important to detoxify H 2 S. Here, we show that SQRD-1 is also required to maintain protein translation in H 2 S. In sqrd-1 mutant animals, exposure to H 2 S leads to phosphorylation of eIF2␣ and inhibition of protein synthesis. In contrast, global protein translation is not altered in wild-type animals exposed to lethally high H 2 S or in hif-1(ia04) mutants that die when exposed to low H 2 S. We demonstrate that both gcn-2 and pek-1 kinases are involved in the H 2 S-induced phosphorylation of eIF2␣. Both ER and mitochondrial stress responses are activated in sqrd-1 mutant animals exposed to H 2 S, but not in wild-type animals. We speculate that SQRD-1 activity in H 2 S may coordinate proteostasis responses in multiple cellular compartments. Hydrogen sulfide (H 2 S)3 is an endogenously produced gas molecule with roles in signaling, neuromodulation, and vasodilation (reviewed in Ref. [1][2][3][4]. Treatment with exogenous H 2 S improves outcome in multiple mammalian models of ischemia/ reperfusion injury (5). However, H 2 S is also toxic at high concentrations, provoking immediate apnea and loss of consciousness that can result in death (6). Industrial exposure to H 2 S is the second-leading cause of death by inhalation, behind only carbon monoxide. The mechanistic differences between beneficial and toxic effects of H 2 S are poorly understood.Sulfide-quinone oxidoreductase (SQRD) is a highly conserved mitochondrial protein that oxidizes cellular H 2 S by transferring electrons to the mitochondrial electron transport chain and adding sulfane sulfur atoms to free sulhydryl moieties (Fig. 1A) (7-9). Isolated mitochondria from chicken liver and human cells can generate ATP when exposed to H 2 S as a result of SQRD activity, which is considered an important aspect of cellular sulfide detoxification (10 -12). However, it is now clear that protein activity can be regulated by post-translational modification by sulfide, and this may be an important aspect of the cellular signaling roles of H 2 S (2, 4). SQRD is therefore positioned to modulate both signaling and toxicity of H 2 S in animals.The nematode Caenorhabditis elegans has a single orthologue of SQRD, sqrd-1. SQRD-1 localizes to mitochondria and is essential for animals to survive exposure to even low concentrations of H 2 S (13). Here, we show SQRD-1 activity is required to prevent activation of the integrated stress response upon exposure to H 2 S. We found that the translation initiation factor eIF2␣ is phosphorylated by both PEK-1 and GCN-2 kinases in sqrd-1 mu...

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Horsman¹,

Miller

2016

Journal of Biological Chemistry

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“…Although regulation of animal PHD activity by iron availability is well-established [cobaltous ion induced erythropoiesis is proposed to be via PHD inhibition (41)], it has had less prominence. P. aeruginosa infections, which often occur in hypoxic niches, such as in the cystic fibrosis lung (42), can induce a HIF-mediated hypoxic response in eukaryotic cells by production of small molecule factors, which have been proposed to be cyanide (43). Pyocyanin induces HIF-α up-regulation in human cells (13), likely via PHD inhibition, at least in part by iron sequestration.…”

Section: Discussionmentioning

confidence: 99%

Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Scotti

Leung

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The roles of 2-oxoglutarate (2OG)-dependent prolyl-hydroxylases in eukaryotes include collagen stabilization, hypoxia sensing, and translational regulation. The hypoxia-inducible factor (HIF) sensing system is conserved in animals, but not in other organisms. However, bioinformatics imply that 2OG-dependent prolyl-hydroxylases (PHDs) homologous to those acting as sensing components for the HIF system in animals occur in prokaryotes. We report cellular, biochemical, and crystallographic analyses revealing that Pseudomonas prolyl-hydroxylase domain containing protein (PPHD) contain a 2OG oxygenase related in structure and function to the animal PHDs. A Pseudomonas aeruginosa PPHD knockout mutant displays impaired growth in the presence of iron chelators and increased production of the virulence factor pyocyanin. We identify elongation factor Tu (EF-Tu) as a PPHD substrate, which undergoes prolyl-4-hydroxylation on its switch I loop. A crystal structure of PPHD reveals striking similarity to human PHD2 and a Chlamydomonas reinhardtii prolyl-4-hydroxylase. A crystal structure of PPHD complexed with intact EF-Tu reveals that major conformational changes occur in both PPHD and EF-Tu, including a >20-Å movement of the EF-Tu switch I loop. Comparison of the PPHD structures with those of HIF and collagen PHDs reveals conservation in substrate recognition despite diverse biological roles and origins. The observed changes will be useful in designing new types of 2OG oxygenase inhibitors based on various conformational states, rather than active site iron chelators, which make up most reported 2OG oxygenase inhibitors. Structurally informed phylogenetic analyses suggest that the role of prolylhydroxylation in human hypoxia sensing has ancient origins.T he hypoxia-inducible transcription factor (HIF) is a major regulator of the response to limited oxygen availability in humans and other animals (1-3). A hypoxia-sensing component of the HIF system is provided by 2-oxoglutarate (2OG)-dependent and Fe(II)-dependent oxygenases, which catalyze prolyl-4-hydroxylation of HIF-α subunits, a posttranslational modification that enhances binding of HIF-α to the von Hippel-Lindau protein (pVHL), so targeting HIF-α for proteasomal degradation. The HIF prolyl-hydroxylases (PHDs) belong to a subfamily of 2OG oxygenases that catalyze prolyl-hydroxylation, which also includes the collagen prolyl-3-hydroxylases (CP3Hs) and prolyl-4-hydroxylases (CP4Hs) (4). Subsequently identified prolyl-hydroxylases include the ribosomal prolyl-hydroxylases (OGFOD1 and Tpa1), which catalyze ribosomal protein 23 prolyl-3-hydroxylation in many eukaryotes, and slime-mold enzymes, which catalyze prolyl-4-hydroxylation of Skp1, a ubiquitin ligase subunit (5-9). The HIF-PHD-VHL triad is likely present in all animals, but probably not in other organisms (3). However, structurally informed bioinformatic analyses imply the presence of PHD homologs in bacteria (10, 11), including in Pseudomonas spp, suggesting PHDs may have ancient origins. ResultsPseudomonas spp. Cont...

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“…The same effect was seen whether the exposure was to 2mM sodium metabisulfite for 48 hours or 30 mM sodium metabisulfite overnight. Exposure to hydrogen sulfide at the non-lethal concentration of 150 ppm causes a reversible state of suspended animation in C. elegans [242]. In order to test for reversible suspended animation in nematodes in response to a non-lethal exposure to sulfur dioxide a DSLR camera with a macro lens was used to take images in quick succession, which allowed for a more detailed analysis of behavior than is possible using WormScan (Appendix 5).…”

Section: Resultsmentioning

confidence: 99%

“…Exposure to H 2 S has also been shown to induce a reversible state of decreased metabolic rate and temperature and a reversible state of suspended animation in mice [37]. This reversible state of suspended animation in C. elegans [242]. Prolonged exposure to a slow-releasing H 2 S donor (GYY4137) results in cancer cell death [243,244], via a defective pH regulation that triggers an uncontrolled intracellular acidification, causing apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Sydney Brenner undertook a selection screen in C. elegans in 1974 to improve understanding of Acetylcholine, which as stated in Chapter 1 stimulates production of the gasotransmitter NO [149]. A forward genetic screen was also undertaken by the Roth laboratory, which identified C. elegans mutants hypersensitive to the gasotransmitter H 2 S [242].…”

Section: Introductionmentioning

confidence: 99%

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Developing high-throughput methods for C. elegans to better understand the newly discovered gasotransmitter sulfur dioxide

Mathew¹

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Sulfur Dioxide (SO 2 ) is the most recently discovered gasotransmitter. As a result there is a significant gap in the literature compared to the other established gasotransmitters which have had several decades of research. Initially, SO 2 was thought to be a toxic air pollutant and byproduct from the metabolism of sulphur containing amino acids. It is thus important to understand its mechanism of action and molecular targets of SO 2 . The pathways for metabolism of sulfur containing gasotransmitters (hydrogen sulfide and sulfur dioxide) in lower organisms was previously unknown. My thesis goal is to gain a better understanding of the function and metabolism of SO 2 . To better elucidate this function I have used the eukaryotic model organisms; Saccharomyces cerevisiae (S. cerevisiae) and Caenorhabditis elegans (C. elegans).Two high-throughput methods were developed as part of this research to improve detail and accuracy of analysis in C. elegans. The first method developed was WormScan, which allowed for automatic whole organism phenotyping. The second method developed was pHi nanoparticles, to enable the characterization of intracellular pH (pHi). These two C. elegans methods were published in PLOS ONE, 2012 and Analytical Biochemistry, 2014. WormScan is based on an affordable consumer grade flatbed scanner that facilitates the quantification of the four main toxicological endpoints of C. elegans and greatly reduces the user bias associated with manual counting. The light intensity produced by the scanner was sufficient to cause negative phototaxis equivalent to a physical stimulus for mortality determination. The affordability and high-throughput nature of WormScan also enable high-throughput whole animal drug screening in C. elegans. The pHi nanoparticles were generated through a modified Stöber synthesis and easily calibrated externally to the C. elegans. The nanoparticles were taken up during feeding, and found to bypass the selective intestinal uptake and translocate to the primary organs and secondary organs of the reproductive tract. This was the first diagnostic use of nanoparticles in C. elegans.It was found that the hypoxia-inducible factor-1 (hif-1) transcription factor was required in order for C. elegans to survive exposure to SO 2 . HIF-1 is a regulator of both pHi homeostasis and metabolic rate. When C. elegans are exposed to a non-lethal concentration of SO 2 , it induced a reversible state of suspended animation, a condition that is characterized by metabolic suppression. A physiologically relevant drop of 0.15 pH units was observed in response to SO 2 exposure. Where such a decrease in pHi is a characteristic of reduced metabolism.II A forward genetic screen was carried out in C. elegans to identify mutations that conferred resistance to SO 2 . A resistance mutation was mapped to a region of Chromosome III using an as yet unpublished high-throughput technique (Mip-Map). Together with whole genome sequencing the gene F08F8.9 causing resistance was identified. The F08F8.9 gene is hom...

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The Response of Caenorhabditis elegans to Hydrogen Sulfide and Hydrogen Cyanide

Cited by 76 publications

References 46 publications

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Developing high-throughput methods for C. elegans to better understand the newly discovered gasotransmitter sulfur dioxide

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