Contribution of NRF2 to sulfur metabolism and mitochondrial activity

Alam, Md. Morshedul; Kishino, Akiyoshi; Sung, Eunkyu; Sekine, Hiroshi; Abe, Takaaki; Murakami, Shohei; Akaike, Takaaki; Motohashi, Hozumi

doi:10.1016/j.redox.2023.102624

Cited by 17 publications

(11 citation statements)

References 51 publications

(68 reference statements)

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“…Notably, the membrane potential that was significantly impaired by SQR KD was found to be almost completely recovered by the TTS treatment to a level similar to that of the WT MEFs. The activity of TTS in this case might be explained by: 1) TTS could detoxify H 2 S by rapidly removing H 2 S from cellular media, and/or 2) the persulfide or H 2 S 2 generated via the TTS reaction might mediate sulfur respiration, as proposed by several studies reported recently 11 , 48 , 50 . All these results suggest that TTS may be able to counteract some characteristics of SQR deficiency, and this might have some interesting applications.…”

Section: Resultsmentioning

confidence: 68%

“…In cells, sulfide:quinone oxidoreductase (SQR) is one of the key enzymes responsible for H 2 S metabolism. SQR catalyzes the two-electron oxidation of H 2 S to form sulfane sulfurs (S 0 ) via persulfide and H 2 S 2 intermediates 46 – 48 . Since TTS could promote the conversion of H 2 S to H 2 S 2 , we envisioned that TTS might be able to offset some features of SQR deficiency.…”

Section: Resultsmentioning

confidence: 99%

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2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

Cui,

Shieh,

Pan

et al. 2024

Nat Commun

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Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

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Section: Resultsmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

Cui,

Shieh,

Pan

et al. 2024

Nat Commun

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“…Therefore, the activity of SQOR may also influence cellular energy production. In conclusion, the enzyme SQOR, encoded by the SQOR gene, plays a crucial role in cellular sulfide metabolism and energy metabolism ( 64 ). Glucocorticoids may influence sulfide metabolism and mitochondrial function by regulating the expression of the SQOR gene.…”

Section: Discussionmentioning

confidence: 99%

Identification and analysis of mitochondria-related central genes in steroid-induced osteonecrosis of the femoral head, along with drug prediction

Ma,

Sun,

Jiang

et al. 2024

Front. Endocrinol.

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PurposeSteroid-induced osteonecrosis of the femoral head (SONFH) is a refractory orthopedic hip joint disease that primarily affects middle-aged and young individuals. SONFH may be caused by ischemia and hypoxia of the femoral head, where mitochondria play a crucial role in oxidative reactions. Currently, there is limited literature on whether mitochondria are involved in the progression of SONFH. Here, we aim to identify and validate key potential mitochondrial-related genes in SONFH through bioinformatics analysis. This study aims to provide initial evidence that mitochondria play a role in the progression of SONFH and further elucidate the mechanisms of mitochondria in SONFH.MethodsThe GSE123568 mRNA expression profile dataset includes 10 non-SONFH (non-steroid-induced osteonecrosis of the femoral head) samples and 30 SONFH samples. The GSE74089 mRNA expression profile dataset includes 4 healthy samples and 4 samples with ischemic necrosis of the femoral head. Both datasets were downloaded from the Gene Expression Omnibus (GEO) database. The mitochondrial-related genes are derived from MitoCarta3.0, which includes data for all 1136 human genes with high confidence in mitochondrial localization based on integrated proteomics, computational, and microscopy approaches. By intersecting the GSE123568 and GSE74089 datasets with a set of mitochondrial-related genes, we screened for mitochondrial-related genes involved in SONFH. Subsequently, we used the good Samples Genes method in R language to remove outlier genes and samples in the GSE123568 dataset. We further used WGCNA to construct a scale-free co-expression network and selected the hub gene set with the highest connectivity. We then intersected this gene set with the previously identified mitochondrial-related genes to select the genes with the highest correlation. A total of 7 mitochondrial-related genes were selected. Next, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on the selected mitochondrial-related genes using R software. Furthermore, we performed protein network analysis on the differentially expressed proteins encoded by the mitochondrial genes using STRING. We used the GSEA software to group the genes within the gene set in the GSE123568 dataset based on their coordinated changes and evaluate their impact on phenotype changes. Subsequently, we grouped the samples based on the 7 selected mitochondrial-related genes using R software and observed the differences in immune cell infiltration between the groups. Finally, we evaluated the prognostic significance of these features in the two datasets, consisting of a total of 48 samples, by integrating disease status and the 7 gene features using the cox method in the survival R package. We performed ROC analysis using the roc function in the pROC package and evaluated the AUC and confidence intervals using the ci function to obtain the final AUC results.ResultsIdentification and analysis of 7 intersecting DEGs (differentially expressed genes) were obtained among peripheral blood, cartilage samples, hub genes, and mitochondrial-related genes. These 7 DEGs include FTH1, LACTB, PDK3, RAB5IF, SOD2, and SQOR, all of which are upregulated genes with no intersection in the downregulated gene set. Subsequently, GO and KEGG pathway enrichment analysis revealed that the upregulated DEGs are primarily involved in processes such as oxidative stress, release of cytochrome C from mitochondria, negative regulation of intrinsic apoptotic signaling pathway, cell apoptosis, mitochondrial metabolism, p53 signaling pathway, and NK cell-mediated cytotoxicity. GSEA also revealed enriched pathways associated with hub genes. Finally, the diagnostic value of these key genes for hormone-related ischemic necrosis of the femoral head (SONFH) was confirmed using ROC curves.ConclusionBID, FTH1, LACTB, PDK3, RAB5IF, SOD2, and SQOR may serve as potential diagnostic mitochondrial-related biomarkers for SONFH. Additionally, they hold research value in investigating the involvement of mitochondria in the pathogenesis of ischemic necrosis of the femoral head.

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“…More recently, it has been demonstrated that a substantial portion of sulfur metabolites contain sulfane sulfur and polymeric sulfur, i.e., catenated sulfur, such as in cysteine persulfide and glutathione trisulfide [ 17 , 18 ]. The inorganic and organic sulfur with sulfur catenation is called supersulfides (RSSnH, n > 1, R = hydrogen or alkyl), which have been recognized as a new entity of biomolecules involved in various biological processes including antioxidant function [ 18 ], anti-inflammatory function [ 19 ], signal transduction [ 20 ], and mitochondrial activation [ 17 , 21 ]. Although previous studies reported that xCT-deficient peritoneal macrophages (xCT-KO PMs) exhibit impaired nitric oxide production and decreased viability after long-term culture [ 22 , 23 ], suggesting substantial requirement of cysteine for macrophage function, how sulfur metabolites, including supersulfides, impact macrophage behavior remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop

et al. 2023

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Contribution of NRF2 to sulfur metabolism and mitochondrial activity

Cited by 17 publications

References 51 publications

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

Identification and analysis of mitochondria-related central genes in steroid-induced osteonecrosis of the femoral head, along with drug prediction

Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop

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