Increased protein aggregation in Zucker Diabetic Fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide

Talaei, Fatemeh; Praag, Veroniek M. van; Shishavan, Mahdi Hamidi; Landheer, Sjoerd W.; Buikema, Hendrik; Henning, Robert H.

doi:10.1186/1471-2121-15-1

Cited by 34 publications

(27 citation statements)

References 68 publications

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“…Similarly, H 2 S alleviates protein aggregation in the forebrain of Zucker Diabetic Fatty Rats (38). Recently, H 2 S signaling has also been shown to mediate at least some aspects of dietary restriction, which reduces the age-associated decline in proteostasis (39 -41).…”

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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“…Telomere-mediated movement along the nuclear envelope is crucial for homologous pairing and synapsis during meiosis (108). Meiotic telomeres carry a set of specific proteins such as SUN1, SUN2 and TERB1, which associate with telomeres between the leptotene and diplotene stages during meiotic prophase I (109,110). The telomere fusion during meiosis in our study could be associated with altered function of these telomere-associated proteins.…”

Section: Discussionmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.

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“…NaHS treatment suppresses the increased protein synthesis and aggregation in cultured brain slices from Zucker diabetic rats, normalizing proteostasis and counteracting oxidative stress [142]. NaHS inhibited the formation of advanced glycation end products, which disrupt proteostasis, in human neuroblastoma SH-SY5Y cells exposed to D-galactose [143].…”

Section: Hydrogen Sulfide and Agingmentioning

confidence: 99%

The role of hydrogen sulfide in aging and age-related pathologies

Perridon

Leuvenink

Hillebrands

et al. 2016

Aging

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When humans grow older, they experience inevitable and progressive loss of physiological function, ultimately leading to death. Research on aging largely focuses on the identification of mechanisms involved in the aging process. Several proposed aging theories were recently combined as the ‘hallmarks of aging’. These hallmarks describe (patho-)physiological processes that together, when disrupted, determine the aging phenotype. Sustaining evidence shows a potential role for hydrogen sulfide (H2S) in the regulation of aging.Nowadays, H2S is acknowledged as an endogenously produced signaling molecule with various (patho-) physiological effects. H2S is involved in several diseases including pathologies related to aging. In this review, the known, assumed and hypothetical effects of hydrogen sulfide on the aging process will be discussed by reviewing its actions on the hallmarks of aging and on several age-related pathologies.

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Increased protein aggregation in Zucker Diabetic Fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide

Cited by 34 publications

References 68 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

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

The role of hydrogen sulfide in aging and age-related pathologies

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