Journal articles: 'MTCH2'

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Manjunath, Lekha E., Anumeha Singh, Sarthak Sahoo, Ashutosh Mishra, Jinsha Padmarajan, Chaithanya G. Basavaraju, and Sandeep M. Eswarappa. "Stop codon read-through of mammalian MTCH2 leading to an unstable isoform regulates mitochondrial membrane potential." Journal of Biological Chemistry 295, no. 50 (October 7, 2020): 17009–26. http://dx.doi.org/10.1074/jbc.ra120.014253.

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Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3′ UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3′ UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

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Guna, Alina, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, et al. "MTCH2 is a mitochondrial outer membrane protein insertase." Science 378, no. 6617 (October 21, 2022): 317–22. http://dx.doi.org/10.1126/science.add1856.

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In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.

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Khan, Dilshad H., Michael Mullokandov, Yan Wu, Marcela Gronda, Rose Hurren, Xiaoming Wang, Neil MacLean, Rob C. Laister, Atan Gross, and Aaron D. Schimmer. "The Mitochondrial Carrier Homolog 2 (MTCH2) Regulates the Differentiation of AML Cells By Influencing the Localization of Pyruvate Dehydrogenase Complex and H3 and H4 Histone Acetylation." Blood 128, no. 22 (December 2, 2016): 1562. http://dx.doi.org/10.1182/blood.v128.22.1562.1562.

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Abstract Mitochondrial carrier homolog 2 (MTCH2) is a mitochondrial outer membrane protein that functions as a receptor-like protein for pro-apoptotic BID. In addition to its role in apoptosis, recent findings show that MTCH2 also regulates cellular metabolism. In murine hematopoietic cells, loss of MTCH2 increases oxidative phosphorylation and reduces the number of hematopoietic stem cells. Here, we sought to understand the role of MTCH2 in leukemogenesis and knocked down MTCH2 in leukemia cell lines using multiple independent shRNAs. Knockdown of MTCH2 reduced growth and viability of AML cells: OCI-AML2 (>90%), TEX (>80%), U937 (>65%), and HL60 (>75%). MTCH2 knockdown also decreased the clonogenic growth of OCI-AML2 (>60%), TEX (>70%), and U937 (>40%) cells compared to controls. However, MTCH2 knockdown did not induce cell death as indicated by annexin V/PI staining. In addition, knockdown of MTCH2 in TEX cells reduced engraftment into the marrow of non-obese diabetic/severe combined immunodeficiency-growth factor (NOD/SCID-GF) mice (control 17±4%, n=10) vs. sh-MTCH2 (4±0.86%, n=10). In mouse models, knockout of MTCH2 decreased the leukomogenic potential of murine hematopoietic stem cells transformed with the MLL-AF9 oncogene and increased the survival of these mice. To understand the mechanism by which MTCH2 knockdown decreased cell growth, we used genome wide transcriptome analysis with RNA-seq and observed an up regulation of genes involved in cellular differentiation. Consistent with increased MTCH2 knockdown promoting differentiation, OCI-AML2 cells with MTCH2 knockdown displayed increased non-specific esterase staining. Increased differentiation (Lin+ve cells) was also observed in MLL-AF9 with MTCH2 knockout. Knockdown of MTCH2 in TEX and OCI-AML2 cells increased levels of H3 and H4 histone acetylation as demonstrated by immunoblotting. Of note, differentiation and increased H3 and H4 acetylation was not observed after inhibiting other mitochondrial processes, such as mitochondrial protein synthesis or mitochondrial DNA replication. Although MTCH2 is a receptor for BID, the increased H3 and H4 acetylation appeared independent of BID as small molecule BID inhibitors did not alter H3 and H4 acetylation. MTCH2 regulates cell metabolism. Therefore, we measured changes in intracellular metabolites in AML cells after MTCH2 knockdown. In AML cells, MTCH2 knockdown increased levels of lactate (2 fold), but did not change the basal rate of oxygen consumption or the activity of mitochondrial respiratory chain complexes. Loss of mitochondrial pyruvate dehydrogenase complex increases lactate levels and a recent study reported that the translocation of pyruvate dehydrogenase complex from the mitochondria to the nucleus under conditions of mitochondrial stress, increases H3 and H4 histone acetylation (Cell. 2014; 158(1):84-97). Therefore, we measured changes in the localization of pyruvate dehydrogenase complex after MTCH2 knockdown. Knockdown of MTCH2 decreased mitochondrial and increased nuclear dehydrogenase complex in OCI-AML2 and TEX cells. Thus, in summary, MTCH2 regulates the differentiation of AML cells and controls the localization of pyruvate dehydrogenase complex and histone acetylation. These results also suggest a mechanism by which loss of MTCH2 leads to reductions of normal hematopoietic stem cells. Disclosures Schimmer: Novartis: Honoraria.

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Kulyté, Agné, Mikael Rydén, Niklas Mejhert, Elisabeth Dungner, Eva Sjölin, Peter Arner, and Ingrid Dahlman. "MTCH2 in Human White Adipose Tissue and Obesity." Journal of Clinical Endocrinology & Metabolism 96, no. 10 (October 1, 2011): E1661—E1665. http://dx.doi.org/10.1210/jc.2010-3050.

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Abstract Context: Genome-wide association studies have identified single-nucleotide polymorphisms in approximately 40 loci associated with obesity-related traits. How these loci regulate obesity is largely unknown. One obesity-associated single-nucleotide polymorphism is close to the MTCH2 gene (mitochondrial carrier homolog 2). Objective: The objective of the study was to assess the expression of genes in obesity-associated loci in abdominal sc white adipose tissue (scWAT) in relation to obesity. A more comprehensive expression study was performed on MTCH2. Design: mRNA levels of 66 genes from 40 loci were determined by microarray in scWAT from lean and obese women (n = 30). MTCH2 mRNA was measured by quantitative RT-PCR in lean and obese before and after weight loss in intact adipose pieces and isolated adipocytes, paired samples of scWAT and omental WAT, and primary adipocyte cultures (n = 191 subjects in total). MTCH2 genotypes were compared with mRNA expression in 96 women. MTCH2 protein was examined in scWAT of 38 individuals. Results: Adipose expression of eight genes was significantly associated with obesity; of these, MTCH2 displayed the highest absolute signal. MTCH2 mRNA and protein expression was significantly increased in obese women but was not affected by weight loss. MTCH2 was enriched in isolated fat cells and increased during adipocyte differentiation. There was no cis influence of MTCH2 genotypes on mRNA levels. Conclusion: MTCH2 is highly expressed in human WAT and adipocytes with increased levels in obese women. These results suggest that MTCH2 may play a role in cellular processes underlying obesity.

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Dudko, H. V., V. A. Urban, and V. G. Veresov. "Molecular mechanisms of high-affinity interaction of the protein tBid with the mitochondrial complex МТСН2-МОАР-1." Doklady of the National Academy of Sciences of Belarus 64, no. 2 (May 17, 2020): 193–98. http://dx.doi.org/10.29235/1561-8323-2020-64-2-193-198.

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Mitochondrial carrier homolog 2 (MTCH2) is a protein that plays an important role in the execution of apoptosis being a receptor for tBid in the outer membrane of mitochondria. Previously, it has been shown that the binding of the modulator of apoptosis-1 (MOAP-1) protein to MTCH2 is required for the efficient MTCH2-mediated recruitment of tBid to mitochondria and, in contrast, tBid is required for the MOAP-1 recruitment to mitochondria, but the structure understanding of these phenomena is absent. In this study, we have provided structural insights into the mechanisms of regulation of the MTCH2 receptor function for tBid by MOAP-1.

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Grinberg, Michal, Michal Schwarz, Yehudit Zaltsman, Tzipi Eini, Hagit Niv, Shmuel Pietrokovski, and Atan Gross. "Mitochondrial Carrier Homolog 2 Is a Target of tBID in Cells Signaled To Die by Tumor Necrosis Factor Alpha." Molecular and Cellular Biology 25, no. 11 (June 1, 2005): 4579–90. http://dx.doi.org/10.1128/mcb.25.11.4579-4590.2005.

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ABSTRACT BID, a proapoptotic BCL-2 family member, plays an essential role in the tumor necrosis factor alpha (TNF-α)/Fas death receptor pathway in vivo. Activation of the TNF-R1 receptor results in the cleavage of BID into truncated BID (tBID), which translocates to the mitochondria and induces the activation of BAX or BAK. In TNF-α-activated FL5.12 cells, tBID becomes part of a 45-kDa cross-linkable mitochondrial complex. Here we describe the biochemical purification of this complex and the identification of mitochondrial carrier homolog 2 (Mtch2) as part of this complex. Mtch2 is a conserved protein that is similar to members of the mitochondrial carrier protein family. Our studies with mouse liver mitochondria indicate that Mtch2 is an integral membrane protein exposed on the surface of mitochondria. Using blue-native gel electrophoresis we revealed that in viable FL5.12 cells Mtch2 resides in a protein complex of ca. 185 kDa and that the addition of TNF-α to these cells leads to the recruitment of tBID and BAX to this complex. Importantly, this recruitment was partially inhibited in FL5.12 cells stably expressing BCL-XL. These results implicate Mtch2 as a mitochondrial target of tBID and raise the possibility that the Mtch2-resident complex participates in the mitochondrial apoptotic program.

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Khan, Dilshad H., Michael Mullokandov, Yan Wu, Veronique Voisin, Marcela Gronda, Rose Hurren, Xiaoming Wang, et al. "Mitochondrial carrier homolog 2 is necessary for AML survival." Blood 136, no. 1 (July 2, 2020): 81–92. http://dx.doi.org/10.1182/blood.2019000106.

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Abstract Through a clustered regularly insterspaced short palindromic repeats (CRISPR) screen to identify mitochondrial genes necessary for the growth of acute myeloid leukemia (AML) cells, we identified the mitochondrial outer membrane protein mitochondrial carrier homolog 2 (MTCH2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells, and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase (PDH), which induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.

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Cogliati, Sara, and Luca Scorrano. "A BID on mitochondria with MTCH2." Cell Research 20, no. 8 (July 13, 2010): 863–65. http://dx.doi.org/10.1038/cr.2010.100.

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Gross, Atan. "MTCH2: A new player in mitochondria biology." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1857 (August 2016): e14. http://dx.doi.org/10.1016/j.bbabio.2016.04.382.

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Moyer, Sydney M., Nina Ilic, Sydney Gang, Taylor E. Arnoff, and William C. Hahn. "Abstract 2361: MYC-driven breast cancer tumorigenesis is dependent on normal mitochondrial function." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2361. http://dx.doi.org/10.1158/1538-7445.am2022-2361.

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Abstract While the transcription factor MYC is amplified in all breast cancer subtypes, nearly 60% of patients with triple-negative tumors have elevated MYC copy number and expression. Patients with triple-negative breast cancer (TNBC) typically have increased metastasis, decreased response to therapies, and poor outcomes, highlighting MYC’s causal association with disease aggressiveness and low survival rates. Unfortunately, MYC is not considered directly pharmacologically tractable. Therefore, we sought to identify collateral “genetic dependencies,” downstream of oncogenic MYC. Using comparative genome-scale CRISPR/Cas9 screening in isogenic human mammary epithelial cells (HMECs), we have identified two mitochondrial membrane transporter genes, TIMM17A and MTCH2, specifically required for MYC-dependent proliferation and survival. Since MYC is suspected to drive metabolic reprogramming in cancers, we assessed how MYC affected mitochondrial protein content by quantitative mass spectrometry. This revealed an increase in N-acetylaspartate (NAA) in HMECs with MYC amplification compared to other genetic backgrounds. Interestingly, increased NAA levels are dependent on TIMM17A and MTCH2 presence. Loss of either of these genes results in cell death coupled with decreased NAA. NAA supplementation in the media of MYC-HMECs following loss of TIMM17A or MTCH2 can rescue the cell death. Importantly, NAA supplementation in cells with guides targeting GFP (negative control) or general essential gene RPL11 did not show increased cell growth/viability - showing that the NAA supplementation is specifically compensating for loss of mitochondrial transport function in MYC-HMECs. Based on these data, it appears that MYC-amplified TNBCs are uniquely dependent on TIMM17A and MTCH2 mitochondrial transporter function because they drive metabolic reprogramming resulting in addiction to N-acetylaspartate production. To conclude these studies, we are evaluating the dependence on mitochondrial transport and NAA synthesis in MYC-amplified TNBCs by assessing the function of TIMM17A and MTCH2 as MYC-specific genetic dependencies in patient derived xenografts of TNBC and determining if TNBCs are addicted to increased NAA synthesis by overexpressing aspartoacylase to breakdown NAA. Successful completion of this work will provide novel drug targets required for survival of aggressive MYC-amplified breast cancers. Citation Format: Sydney M. Moyer, Nina Ilic, Sydney Gang, Taylor E. Arnoff, William C. Hahn. MYC-driven breast cancer tumorigenesis is dependent on normal mitochondrial function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2361.

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Gross*, Atan, Alan J. Robinson, and Edmund R. S. Kunji. "Establishing the role of the mitochondrial carrier MTCH2." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (July 2010): 44. http://dx.doi.org/10.1016/j.bbabio.2010.04.148.

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Rottiers, Veerle, Adam Francisco, Michael Platov, Yehudit Zaltsman, Antonella Ruggiero, Siu Sylvia Lee, Atan Gross, and Sergiy Libert. "MTCH2 is a conserved regulator of lipid homeostasis." Obesity 25, no. 3 (January 27, 2017): 616–25. http://dx.doi.org/10.1002/oby.21751.

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Raemy, E., S. Montessuit, S. Pierredon, A. H. van Kampen, F. M. Vaz, and J.-C. Martinou. "Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis." Cell Death & Differentiation 23, no. 7 (January 22, 2016): 1165–74. http://dx.doi.org/10.1038/cdd.2015.166.

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Zhao, Yijing, Jiuwei Cui, Jifan Hu, and Andrew R. Hoffman. "Effect of MALAT1 in the crosstalk between nucleus and mitochondria on mitochondrial reprogramming in hepatocellular carcinoma cells." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14711-e14711. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14711.

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e14711 Background: Mitochondria-nuclear crosstalk is a bidirectional pathway of communication between mitochondria and nucleus that influences many cellular and organismal activities. This crosstalk can regulate several oncogenic pathways involved in tumorigenesis. MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), a nucleus-encoded lncRNA, dysregulated in multiple human malignancies is recently found to drive mitochondria dysfunction in Mitochondria-nuclear crosstalk. Methods: RNA sequencing, “RNA reverse transcription-associated trap sequencing” (RAT-seq), RNA immunoprecipitation(RIP), fluorescence in situ hybridization (FISH), were performed to detect the position of the MALAT1, and its interaction protein and DNAs in HepG2 cell line. After silencing MALAT1 by shRNAs, Seahorse, ATP production, lysotracker staining, Western blot, and electronic microscope were used to measure metabolism, ROS amount, mitophagy, apoptosis and mitochondrial morphology of the silencing cell lines. Results: By combining mitochondrial RNA-Seq with FISH, it is surprised to discover that MALAT1 was enriched in the mitochondria of HepG2 cells. Using RAT-seq approach, MALAT1 was found to utilized it 3’-fragment to interact with multiple loci of mitochondrial DNA( D-loop, COX2, ND3, and CYTB ). The RIP and affinity RNA pulldown assays suggested that the RNA-binding protein HuR mediated the transportation of MALAT1 to the mitochondria. Also, mitochondria transmembrane protein mitochondrial carrier 2(MTCH2) is found to interacted MALAT1, suggesting that MALAT1 may through the MTCH2 to get into the inside of the mitochondria. Knockdown of MALAT1 induced multiple abnormalities in mitochondrial functions, including low OXPHOS, low ATP production, reduced mitophagy, declined mtDNA copy number, and activation of the mitochondrial apoptosis pathway. Conclusions: Together, this study greatly expands our knowledge of the nucleus-encoded lncRNA MALAT1 driving the mitochondria dysfunction. Our study establishes MALAT1 as a regulator through interacting with MT-DNA, HuR, MTCH2 protein, revealing a new regulatory mechanism of mitochondria. Many novel nucleus-encoded RNAs existing in mitochondria were identified at the first time, suggesting novel biological functions of lncRNAs, laying the foundation for further clarifying their roles.

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Zaltsman, Yehudit, Liat Shachnai, Natalie Yivgi-Ohana, Michal Schwarz, Maria Maryanovich, Riekelt H. Houtkooper, Frédéric Maxime Vaz, et al. "MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria." Nature Cell Biology 12, no. 6 (May 2, 2010): 553–62. http://dx.doi.org/10.1038/ncb2057.

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Gross, Atan, Maria Maryanovich, and Yehudit Zaltsman. "A MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate." Experimental Hematology 43, no. 9 (September 2015): S65. http://dx.doi.org/10.1016/j.exphem.2015.06.132.

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Djajawi, Tirta Mario, Lei Liu, Jia-nan Gong, Allan Shuai Huang, Ming-jie Luo, Zhen Xu, Toru Okamoto, Melissa J. Call, David C. S. Huang, and Mark F. van Delft. "MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex." Cell Death & Differentiation 27, no. 8 (February 24, 2020): 2484–99. http://dx.doi.org/10.1038/s41418-020-0517-0.

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G.Veresov, Valery, and Alexander I. Davidovskii. "Structural insights into proapoptotic signaling mediated by MTCH2, VDAC2, TOM40 and TOM22." Cellular Signalling 26, no. 2 (February 2014): 370–82. http://dx.doi.org/10.1016/j.cellsig.2013.11.016.

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Khan, Imran, Esra Büşra Işık, Sadaf Mahfooz, Asif M. Khan, and Mustafa Aziz Hatiboglu. "Identification of Genetic Alterations in Rapid Progressive Glioblastoma by Use of Whole Exome Sequencing." Diagnostics 13, no. 6 (March 7, 2023): 1017. http://dx.doi.org/10.3390/diagnostics13061017.

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Background: Glioblastoma poses an inevitable threat to patients despite aggressive therapy regimes. It displays a great level of molecular heterogeneity and numerous substitutions in several genes have been documented. Next-generation sequencing techniques have identified various molecular signatures that have led to a better understanding of the molecular pathogenesis of glioblastoma. In this limited study, we sought to identify genetic variants in a small number of rare patients with aggressive glioblastoma. Methods: Five tumor tissue samples were isolated from four patients with rapidly growing glioblastoma. Genomic DNA was isolated and whole exome sequencing was used to study protein-coding regions. Generated FASTQ files were analyzed and variants were called for each sample. Variants were prioritized with different approaches and functional annotation was applied for the detrimental variants. Results: A total of 49,780 somatic variants were identified in the five glioblastoma samples studied, with the majority as missense substitutions. The top ten genes with the highest number of substitutions were MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1. Notably, variant prioritization after annotation indicated that the MTCH2 (Chr11: 47647265 A>G) gene sequence change was putative deleterious in all of the aggressive tumor samples. Conclusion: The MTCH2 (Chr11: 47647265 A>G) gene substitution was identified as putative deleterious in highly aggressive glioblastomas, which merits further investigation. Moreover, a high tumor mutation burden was observed, with a signature of the highest substitutions in MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1 genes. The findings provide critical, initial data for the further rational design of genetic screening and diagnostic approaches against aggressive glioblastoma.

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Jiang, Qin, Baofa Sun, Qing Liu, Min Cai, Ruifan Wu, Fengqin Wang, Yongxi Yao, Yizhen Wang, and Xinxia Wang. "MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m 6 A‐YTHDF1‐dependent mechanism." FASEB Journal 33, no. 2 (October 19, 2018): 2971–81. http://dx.doi.org/10.1096/fj.201801393rrr.

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Goldman, Andrés, Rosana Rodríguez-Casuriaga, Evangelina González-López, Carlos A. Capoano, Federico F. Santiñaque, and Adriana Geisinger. "MTCH2 is differentially expressed in rat testis and mainly related to apoptosis of spermatocytes." Cell and Tissue Research 361, no. 3 (March 28, 2015): 869–83. http://dx.doi.org/10.1007/s00441-015-2163-2.

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Bar-Lev, Yamit, Sharon Moshitch-Moshkovitz, Galia Tsarfaty, Dafna Kaufman, Judith Horev, James H. Resau, and Ilan Tsarfaty. "Mimp/Mtch2, an Obesity Susceptibility Gene, Induces Alteration of Fatty Acid Metabolism in Transgenic Mice." PLOS ONE 11, no. 6 (June 30, 2016): e0157850. http://dx.doi.org/10.1371/journal.pone.0157850.

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Buzaglo-Azriel, Liat, Yael Kuperman, Michael Tsoory, Yehudit Zaltsman, Liat Shachnai, Smadar Levin Zaidman, Elad Bassat, et al. "Loss of Muscle MTCH2 Increases Whole-Body Energy Utilization and Protects from Diet-Induced Obesity." Cell Reports 14, no. 7 (February 2016): 1602–10. http://dx.doi.org/10.1016/j.celrep.2016.01.046.

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Buzaglo-Azriel, Liat, Yael Kuperman, Michael Tsoory, Yehudit Zaltsman, Liat Shachnai, Smadar Levin Zaidman, Elad Bassat, et al. "Loss of Muscle MTCH2 Increases Whole-Body Energy Utilization and Protects from Diet-Induced Obesity." Cell Reports 18, no. 5 (January 2017): 1335–36. http://dx.doi.org/10.1016/j.celrep.2017.01.046.

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Arigoni, Maddalena, Giuseppina Barutello, Federica Riccardo, Elisabetta Ercole, Daniela Cantarella, Francesca Orso, Laura Conti, et al. "miR-135b Coordinates Progression of ErbB2-Driven Mammary Carcinomas through Suppression of MID1 and MTCH2." American Journal of Pathology 182, no. 6 (June 2013): 2058–70. http://dx.doi.org/10.1016/j.ajpath.2013.02.046.

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Zhou, Guiqing, Jianhui Liu, Xiangyang Li, Yujian Sang, Yue Zhang, Leqiang Gao, Ji Wang, et al. "Silica nanoparticles inducing the apoptosis via microRNA-450b-3p targeting MTCH2 in mice and spermatocyte cell." Environmental Pollution 277 (May 2021): 116771. http://dx.doi.org/10.1016/j.envpol.2021.116771.

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Katz, Chen, Yehudit Zaltsman-Amir, Yana Mostizky, Neta Kollet, Atan Gross, and Assaf Friedler. "Molecular Basis of the Interaction between Proapoptotic Truncated BID (tBID) Protein and Mitochondrial Carrier Homologue 2 (MTCH2) Protein." Journal of Biological Chemistry 287, no. 18 (March 13, 2012): 15016–23. http://dx.doi.org/10.1074/jbc.m111.328377.

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Jiménez-Osorio, Angélica Saraí, Alma Olivia Aguilar-Lucio, Helios Cárdenas-Hernández, Claudette Musalem-Younes, Jacqueline Solares-Tlapechco, Paula Costa-Urrutia, Oscar Medina-Contreras, Julio Granados, and Martha Eunice Rodríguez-Arellano. "Polymorphisms in Adipokines in Mexican Children with Obesity." International Journal of Endocrinology 2019 (July 1, 2019): 1–5. http://dx.doi.org/10.1155/2019/4764751.

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The high prevalence of childhood obesity in Mexico is alarming in the health-science field. We propose to investigate the contribution of adipokines and cytokines polymorphisms and common BMI/obesity-associated loci, revealed in genome-wide association studies in Caucasian adult cohorts, with childhood obesity. This study included 773 Mexican-Mestizo children (5-15 years old) in a case-control study. The polymorphisms included were ADIPOQ (rs6444174), TNF-α (rs1800750), IL-1β (rs1143643), IL-6 (rs1524107; rs2069845), NEGR1 (rs34305371), SEC16B-RASAL2 (rs10913469), TMEM18 (rs6548238; rs7561317), GNPDA2 (rs16857402), LEP (rs2167270), MTCH2 (rs10838738), LGR4-LIN7C-BDNF (rs925946), BCDIN3D-FAIM2 (rs7138803), FTO (rs62033400), MC4R (rs11872992), MC4R (rs17782313), and KCTD15 (rs29942). No significant contribution was found with adipokines and cytokines polymorphisms in this study. Only both TMEM18 (rs6548238; rs7561317) polymorphisms were found associated with obesity (OR=0.5, P=0.008) and were in linkage disequilibrium (r2=0.87). The linear regression showed that the rs7561317 polymorphism of TMEM18 is negatively associated with obesity. This report highlights the influence of TMEM18 in Mexican-Mestizo children obesity, while adipokine and cytokine polymorphisms were not associated with it.

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Robinson, Alan J., Edmund R. S. Kunji, and Atan Gross. "Mitochondrial carrier homolog 2 (MTCH2): The recruitment and evolution of a mitochondrial carrier protein to a critical player in apoptosis." Experimental Cell Research 318, no. 11 (July 2012): 1316–23. http://dx.doi.org/10.1016/j.yexcr.2012.01.026.

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Harris, Benjamin Howell Lole, Simon Wigfield, Adrian L. Harris, and Francesca Meteora Buffa. "Bioinformatic approaches elucidate a high likelyhood of interaction between miR-182 and the pro-apoptotic gene MTCH2 in breast cancers." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): e12551-e12551. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.e12551.

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Zhou, Xiao, Keji Zhang, Zhengyu He, Yuxiao Deng, and Yuan Gao. "Downregulated miR-150 in bone marrow mesenchymal stem cells attenuates the apoptosis of LPS-stimulated RAW264.7 via MTCH2-dependent mitochondria transfer." Biochemical and Biophysical Research Communications 526, no. 3 (June 2020): 560–67. http://dx.doi.org/10.1016/j.bbrc.2020.03.098.

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Mumby, Hannah S., Cathy E. Elks, Shengxu Li, Stephen J. Sharp, Kay-Tee Khaw, Robert N. Luben, Nicholas J. Wareham, Ruth J. F. Loos, and Ken K. Ong. "Mendelian Randomisation Study of Childhood BMI and Early Menarche." Journal of Obesity 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/180729.

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To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established “BMI-increasing” genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39–77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI-associated common variants (in/nearFTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2andSH2B1), and for each individual a “BMI-increasing-allele-score” was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1 kg/m2increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6–8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche.

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Juliane, Stickel S., Claudia Berlin, Daniel J. Kowalewski, Heiko Schuster, Lothar Kanz, Helmut R. Salih, Hans-Georg Rammensee, and Stefan Stevanovic. "HLA Class I Ligandome Analysis In Acute Myeloid Leukemia – Novel T-Cell Epitopes For Peptide-Based Immunotherapy." Blood 122, no. 21 (November 15, 2013): 5431. http://dx.doi.org/10.1182/blood.v122.21.5431.5431.

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Abstract Data regarding the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (SCT) and donor lymphocyte infusion strongly suggest that T lymphocytes play a major role in the rejection of leukemic cells. Immunotherapy directed against leukemia- associated antigens might elicit specific immune responses that may serve to eliminate minimal residual disease after chemotherapy, or enhance the GVL effect after SCT. To achieve this goal there is need to identify appropriate leukemia associated HLA ligands, which are able to induce specific T cell responses. We here aimed to characterize the HLA class I ligandome in AML patients to provide novel tumor associated antigens (TAA) for peptide-based immunotherapy employing our recently implemented approach of direct isolation and identification of naturally presented HLA ligands by affinity chromatography and mass spectrometry (LC-MS/MS) in AML (Stickel et.al., abstract in Blood 2012). Absolute HLA surface expression on AML cells and autologous monocytes and granulocytes was quantified by flow cytometry. HLA class I ligands were isolated from AML cells as well as bone marrow and peripheral blood mononuclear cell (BMNCs/PBMCs) of healthy donors. LC-MS/MS peptide analysis provided qualitative and semi-quantitative information regarding the composition of the respective ligandomes. Comparative analysis of malignant and benign samples served to identify ligandome-derived TAA (LiTAA) and to select peptide vaccine candidates. The most abundantly detected peptide candidates were checked for immunogenicity by ELISpot and confirmed by intracellular interferon-g staining of CD8+ T-cells. Meanwhile 15 AML patients (8 FLT3-ITD mutant) and 35 healthy donors were analyzed. We observed overexpression of HLA class I and II on AML cells as compared to autologous monocytes and granulocytes, with the level of significance reached for HLA class II (p=0,04). A total of more than 12,000 AML derived HLA ligands representing >6,000 different source proteins were identified; of which 2,220 were exclusively represented in AML, but not in healthy PBMC/BMNC. Data mining for broadly represented LiTAA pinpointed 98 TAA as most promising targets. HLA ligands derived from these TAA were presented exclusively on more than 33% of all analyzed AML samples, amongst them already described TAA (e.g. JUP, FAF1) as well as several new leukemia-associated proteins (e.g. MTCH2, METTL7A). Subset analysis of the FLT3-ITD positive AML cohort revealed 21 LiTAA presented exclusively on more than 50% of FLT3-ITD positive AML cases. Additional screening for HLA ligands derived from described leukemia associated antigens revealed overrepresentation for e.g. FLT3, NUSAP, RHAMM and RGS5. Specific CD8+ T cell responses were detected against two A*03 epitope pools (pool 1: APLP2, DKGZ, FAF1, MTCH2; pool 2: KLF2, METTL7A, VCIP1, WIPI1) in AML patients. Notably, the chosen A*03 epitope pools did not elicit specific responses of CTL from healthy donors. Taken together, our HLA class I ligandome analysis in AML for the first time identified naturally presented HLA ligands from patients including a vast array of new leukemia associated antigens representing promising targets for a multipeptide-based immunotherapy approach in AML. Disclosures: No relevant conflicts of interest to declare.

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Slovak, Marilyn L., Victoria Bedell, Dolores Bobadilla, Norma J. Nowak, Maria L. Delioukina, Lawrence M. Weiss, David Smith, and Stephen J. Forman. "Genomic Alterations in Hodgkin’s and Reed/Sternberg (HRS) Cells at Disease Onset Reveals Distinct Signatures for Chemosensitive and Primary Refractory Hodgkin’s Lymphoma." Blood 112, no. 11 (November 16, 2008): 1451. http://dx.doi.org/10.1182/blood.v112.11.1451.1451.

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Abstract The hallmark of Hodgkin’s Lymphoma (HL) is the presence of large Hodgkin’s and Reed/Sternberg (HRS) cells that comprise only ~1–3% of the cellular infiltrate. Given the paucity of genomic analyses of these cells, we sought to characterize their DNA copy number alterations (CNA) by array comparative genomic hybridization (aCGH) using DNA isolated from laser capture microdissected (LCM) CD30+ HRS cells. Primary paraffin-embedded diagnostic samples were obtained from 27 patients (pts), including 15 pts with chemotherapy responsive and 12 pts with primary refractory HL. From each sample, 150 HRS cells were isolated by LCM from 5-μm thick tissue sections, amplified using whole genome amplification (WGA), and hybridized to a minimal tiling 19K whole genome bacterial artificial chromosome (BAC) array (BAC center to center distance of 165 kb). To define thresholds for calling gains and loss and to control for WGA noise, 1.05 ng DNA (DNA equivalent of 150 cells) was obtained from six normal (3 males and 3 females) individuals, amplified and analyzed by aCGH. Triplicate samples from a single HL pt confirmed mean replicate correlation as approximately Pearson r = 0.90. DNA gains and losses observed in >35% of the HL samples were localized to 22 and12 chromosome regions, respectively. Region-specific FISH analyses confirmed the presence or absence of aCGH-defined CNAs in CD30+ HRS for 10 of these regions (3–5 pt samples/FISH probe). CNA gains in >60% of HL samples included genes associated with growth and proliferation (AHR, BAI1, BOP1, COMMD5, LY6E, PTP4A3, SLURP1, CBFA2T3, SLC7A5, NOTCH1, FOXF1, TRAF2, IRF8, S100B, MYH14), cell cycle (AKT1, CDK10, SUMO3), drug metabolism (CYP11B1, CYP11B2, SLC19A1), angiogenesis and cell adhesion (COL18A1, CDH4, ITGB2), apoptosis regulation (FOXC2, FOXF1, GPR132), immune and lymphatic development (CBFA2T3, IL17C, IRF8, CLEC11A, RXRA, SPIB, ICOSLG) and invasion, metastasis or cancer-relatedness (VAV2, PSCA PTP4A3, GINS2, FUT7, TUBB2C, KLK, POLD1, TFF2). Losses observed in >40% of HL samples included SPRY1, NELL1, SLC1A3, GDNF, IL7R, SKP2, GRIA1, ID4, PPARGC1A, and TXNIP. Different CNA patterns between sensitive and refractory HL were identified. Genomic differences observed either specifically or in >35% of the HL chemosensitive pts included ~25 CNA gains including genes known to regulate T-cell trafficking or NFkB activation (CCL22, CX3CL1, CCL17, DOK4 and IL10). The refractory signature showed a higher frequency of CNA gains for three genes involved in the H4 ubiquitin ligase complex that play a role in the cellular response to DNA damage (HDAC4, CUL4A, and DDB2), and gains of ILKAP, GAS6, MADD, SPI1, PVR, MTCH2 CCND3, GPCI, MAPK11 with CNA losses of ELAC2, IL2, GRIA1, SLC17A6, IL21, and MAP2K4 genes. Of interest, CCL22 and CX3CL1 have been associated with a more favorable outcome and a lower risk of recurrence in other cancers, whereas gains or overexpression of SKP2, MTCH2 and CCND3 have been associated with a poor prognosis and a more aggressive cancer phenotype. Moreover, genomewide discrimination analyses on CNAs revealed two distinct clusters that correlated closely with the favorable and unfavorable IPS scores for the 27 HL pts evaluated. Overall, our proof-of-principle, exploratory genomic analyses of HD show that genomic profiles of small numbers of HRS cells is possible, HL samples shared many CNAs but differences may reflect disease course, and highlights the potential to build a genetic CNA map for HL to potentially guide prognosis, therapy decisions and drug discovery.

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Huang, Ting, Xuan Huang, Yumin Nie, Xiangkui Shi, and Chuanjun Shu. "A Combined Effect of Expression Levels of Obesity-Related Genes and Clinical Factors on Cancer Survival Rate." BioMed Research International 2020 (November 24, 2020): 1–20. http://dx.doi.org/10.1155/2020/8838676.

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Obesity is directly associated with the risk of cancer in different organs, including breast, colon, and kidney. However, adipocytes could be utilized to control progression for some types of cancer, such as leukemia and breast cancer. To explore the potential correlation between adipocytes and cancer, the combined effect of expression levels of obesity-related genes and clinical factors (i.e., gender, race, menopausal status, history of smoking, tumor grade, body mass index (BMI), and history of drinking) on cancer survival rate was systemically studied. The expression levels of obesity-related genes in cancer tissues and normal tissues were downloaded from The Cancer Genome Atlas (TCGA). Kaplan–Meier curves were plotted using R programming language. The log-rank test was applied to explore the correlation between different clinical subgroups. The overexpression of the nine obesity-related genes (MC4R, TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, FTO, PCSK1, and GPR120) may associate with tumor-promoting factors in some organs (head and neck, gastrointestinal tract, liver, and gallbladder). Underexpressed LEPR, NEGR1, TMEM18, and SH2B1 genes prevented the progression and metastasis of kidney cancer. The combined effect of clinical factors and the expression levels of obesity-related genes on patients’ survival was found to be significant. Our outcomes suggested that the alternations of DNA methylation patterns could result in the changes of expression levels of obesity-related genes, playing a critical role in tumor progression. The results of the current study may be utilized to supplement precision and personalized medicine, as well as provide novel insights for the development of treatment approaches for cancer.

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Li, Peng, Lulu Gao, Tongxi Cui, Weiyu Zhang, Zixin Zhao, and Lingyi Chen. "Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair." Proceedings of the National Academy of Sciences 117, no. 5 (January 21, 2020): 2519–25. http://dx.doi.org/10.1073/pnas.1915079117.

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The highly conserved COP9 signalosome (CSN), composed of 8 subunits (Cops1 to Cops8), has been implicated in pluripotency maintenance of human embryonic stem cells (ESCs). Yet, the mechanism for the CSN to regulate pluripotency remains elusive. We previously showed that Cops2, independent of the CSN, is essential for the pluripotency maintenance of mouse ESCs. In this study, we set out to investigate how Cops5 and Cops8 regulate ESC differentiation and tried to establish Cops5 and Cops8 knockout (KO) ESC lines by CRISPR/Cas9. To our surprise, no Cops5 KO ESC clones were identified out of 127 clones, while three Cops8 KO ESC lines were established out of 70 clones. We then constructed an inducible Cops5 KO ESC line. Cops5 KO leads to decreased expression of the pluripotency marker Nanog, proliferation defect, G2/M cell-cycle arrest, and apoptosis of ESCs. Further analysis revealed dual roles of Cops5 in maintaining genomic stability of ESCs. On one hand, Cops5 suppresses the autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis and minimize reactive oxygen species (ROS) production, thereby reducing endogenous DNA damage. On the other hand, Cops5 is required for high DNA damage repair (DDR) activities in ESCs. Without Cops5, elevated ROS and reduced DDR activities lead to DNA damage accumulation in ESCs. Subsequently, p53 is activated to trigger G2/M arrest and apoptosis. Altogether, our studies reveal an essential role of Cops5 in maintaining genome integrity and self-renewal of ESCs by regulating cellular metabolism and DDR pathways.

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Ng, Maggie C. Y., Claudia H. T. Tam, Wing Yee So, Janice S. K. Ho, Alfred W. Chan, Heung Man Lee, Ying Wang, Vincent K. L. Lam, Juliana C. N. Chan, and Ronald C. W. Ma. "Implication of Genetic Variants NearNEGR1,SEC16B,TMEM18,ETV5/DGKG,GNPDA2,LIN7C/BDNF,MTCH2,BCDIN3D/FAIM2,SH2B1,FTO,MC4R, andKCTD15with Obesity and Type 2 Diabetes in 7705 Chinese." Journal of Clinical Endocrinology & Metabolism 95, no. 5 (May 1, 2010): 2418–25. http://dx.doi.org/10.1210/jc.2009-2077.

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Kisaki, Carolina Yukiko, Stephanie Santos Suehiro Arcos, Fabio Montoni, Wellington da Silva Santos, Hamida Macêdo Calacina, Ismael Feitosa Lima, Daniela Cajado-Carvalho, Emer Suavinho Ferro, Milton Yutaka Nishiyama-Jr, and Leo Kei Iwai. "Bothrops Jararaca Snake Venom Modulates Key Cancer-Related Proteins in Breast Tumor Cell Lines." Toxins 13, no. 8 (July 25, 2021): 519. http://dx.doi.org/10.3390/toxins13080519.

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Cancer is characterized by the development of abnormal cells that divide in an uncontrolled way and may spread into other tissues where they may infiltrate and destroy normal body tissue. Several previous reports have described biochemical anti-tumorigenic properties of crude snake venom or its components, including their capability of inhibiting cell proliferation and promoting cell death. However, to the best of our knowledge, there is no work describing cancer cell proteomic changes following treatment with snake venoms. In this work we describe the quantitative changes in proteomics of MCF7 and MDA-MB-231 breast tumor cell lines following treatment with Bothrops jararaca snake venom, as well as the functional implications of the proteomic changes. Cell lines were treated with sub-toxic doses at either 0.63 μg/mL (low) or 2.5 μg/mL (high) of B. jararaca venom for 24 h, conditions that cause no cell death per se. Proteomics analysis was conducted on a nano-scale liquid chromatography coupled on-line with mass spectrometry (nLC-MS/MS). More than 1000 proteins were identified and evaluated from each cell line treated with either the low or high dose of the snake venom. Protein profiling upon venom treatment showed differential expression of several proteins related to cancer cell metabolism, immune response, and inflammation. Among the identified proteins we highlight histone H3, SNX3, HEL-S-156an, MTCH2, RPS, MCC2, IGF2BP1, and GSTM3. These data suggest that sub-toxic doses of B. jararaca venom have potential to modulate cancer-development related protein targets in cancer cells. This work illustrates a novel biochemical strategy to identify therapeutic targets against cancer cell growth and survival.

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Shamas-Din, Aisha, Scott Bindner, Xiaoke Chi, Brian Leber, David W. Andrews, and Cécile Fradin. "Distinct lipid effects on tBid and Bim activation of membrane permeabilization by pro-apoptotic Bax." Biochemical Journal 467, no. 3 (April 17, 2015): 495–505. http://dx.doi.org/10.1042/bj20141291.

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After exposure to stressful stimuli, apoptotic signals can be relayed to mitochondria by pro-apoptotic activator proteins, tBid (truncated Bid/p15) and Bim (Bcl-2 interacting mediator), which activate Bax (Bcl-2 associated X protein) and or Bak (Bcl-2 antagonist/killer) to induce mitochondrial outer membrane (MOM) permeabilization (MOMP). These protein–protein and protein–membrane interactions are critical for apoptosis regulation, since MOMP irreversibly leads to cell death. Whereas the distinct roles of tBid and Bim as sensors of different types of stress are well recognized, it is not known whether the molecular mechanisms whereby they initiate MOMP are the same. In the present study, we compare membrane permeabilization by Bax activated by either cBid [cleaved Bid (p7 and p15)] or Bim and we examine the role of membrane lipids in the recruitment and activation of these three Bcl-2 (B-cell lymphoma 2) pro-apoptotic proteins. We employ fluorescently-labelled proteins and liposomes to quantify the effects of specific lipids on each of the well-characterized steps in Bax-mediated membrane permeabilization. We show that high levels of cholesterol in the membrane inhibit permeabilization by categorically identifying the recruitment of Bax by the activators and Bax insertion in the membrane as the steps being hindered by cholesterol. Furthermore, we show that binding of both cBid and Bim to membranes is facilitated by electrostatic interactions with anionic phospholipids. However, whereas Bim does not require any particular anionic lipids, the conformational change in tBid depends on cardiolipin (CL). This suggests that CL can activate tBid in a similar manner to Mtch2 (mitochondrial carrier homologue 2). Thus, lipids modify multiple aspects of Bax-mediated membrane permeabilization.

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Chen, Guolin, Shanshan Mo, and Di Yuan. "Upregulation Mitochondrial Carrier 1 (MTCH1) Is Associated with Cell Proliferation, Invasion, and Migration of Liver Hepatocellular Carcinoma." BioMed Research International 2021 (June 7, 2021): 1–10. http://dx.doi.org/10.1155/2021/9911784.

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Among the primary causes of cancer-associated death in the world, liver hepatocellular carcinoma (LIHC) ranks the third. LIHC is defined as the sixth most frequently diagnosed carcinoma. The gene mitochondrial carrier 1 (MTCH1) is a protein-coding gene. Recent research suggests that MTCH1 may be associated with some diseases. Here, our study attempts to explore the role and implication of MTCH1 in LIHC. Kaplan Meier Plotter and GEPIA (Gene Expression Profiling Interactive Analysis) databases were employed to determine the expression of MTCH1 and its correlation with prognostic status in LIHC patients. For the first time, our results suggested that MTCH1 was aberrantly expressed in human pan-cancer and highly expressed in LIHC. Its high expression was closely associated with metastasis of tumor, stage of cancer, and poor survival of patients. Then, through enrichment analysis, MTCH1 was found to be closely related to RNA splicing in LIHC. Subsequently, we conducted a series of functional experiments. PCR data showed that LIHC cell lines and samples are highly expressed MTCH1. CCK-8 (Cell Counting Kit-8) assays and Transwell assays indicated that silencing MTCH1 certainly suppressed cell proliferation, migration, and invasion. These findings shed the clue that MTCH1 could be regarded as the potential prognosis biomarker of LIHC and a promising therapeutic target for LIHC.

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Ravindranath, N. H., and Indu K. Murthy. "Mitigation co-benefits of carbon sequestration from MGNREGS in India." PLOS ONE 16, no. 5 (May 20, 2021): e0251825. http://dx.doi.org/10.1371/journal.pone.0251825.

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Mahatma Gandhi Rural Employment Guarantee Scheme a large social security programme being implemented in India, with an average annual investment of US$ 7 billion. The bulk of the activities under this programme are focused on natural resources such as land, water and trees, which provide adaptation benefits. In this study an attempt is made to estimate the carbon sequestration achieved and future potential, as a co-benefit, from MGNREGS. The total mean carbon sequestered at the national level, considering the cumulative number of natural resource based activities, for the year 2017–18 was estimated to be 102 MtCO2. The annual mean carbon sequestration is projected to increase to about 132 MtCO2 by 2020 and 249 MtCO2 by 2030. Drought proofing is one of the activities implemented under MGNREGS and it includes tree planting, relevant to achieving the NDC carbon sink target. The cumulative carbon sink created by drought proofing activities is projected to be 56 MtCO2 in 2020, 281 MtCO2 in 2025 and 561 MtCO2 in 2030. This study demonstrates the significant carbon sink potential of MGNREGS and highlights the importance of estimation and reporting climate mitigation co-benefits of adaptation actions such as MGNREGS under the Paris Agreement.

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D’Angelo, Donato, and Rosario Rizzuto. "The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases." Biomolecules 13, no. 9 (August 25, 2023): 1304. http://dx.doi.org/10.3390/biom13091304.

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Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.

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Obata-Ninomiya, Kazushige, Kenji Ishiwata, Hisanobu Nakano, Yusuke Endo, Tomomi Ichikawa, Atsushi Onodera, Kiyoshi Hirahara, Yoshitaka Okamoto, Hirotaka Kanuka, and Toshinori Nakayama. "CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth." Proceedings of the National Academy of Sciences 115, no. 42 (October 1, 2018): E9849—E9858. http://dx.doi.org/10.1073/pnas.1714731115.

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Memory T helper (mTh) cells play important roles in the reinfection of pathogens and drive the pathogenesis of diseases. While recent studies have characterized the pathogenic mTh2 cell subpopulations driving allergic inflammation, those that induce immune responses against helminth infection remain unknown. We found that IL-5–producing CXCR6+ST2+CD44+ mTh2 cells play a crucial role in the IL-33–dependent inhibition of the fecundity of helminth, whereas other ST2− mTh2 cells do not. Although both cell types induced the infiltration of granulocytes, especially eosinophils, into the lungs in response to helminth infection, the ST2+ mTh2 cell-induced eosinophils expressed higher levels of major basic protein (MBP), which is important for reducing the fecundity of Nippostrongylus brasiliensis (Nb), than ST2− mTh2 cell-induced ones. Notably, we also found that ST2+ Treg cells but not ST2− Treg cells suppressed CXCR6+ST2+ mTh2 cell-mediated immune responses. Taken together, these findings show that we identified a mechanism against helminth elicited by a subpopulation of IL-5–producing mTh2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs.

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Liu, Xiaoyu, Xian’en Wang, Junnian Song, Haiyan Duan, and Shuo Wang. "Why Are the Carbon Footprints of China’s Urban Households Rising? An Input–Output Analysis and Structural Decomposition Analysis." Sustainability 11, no. 24 (December 13, 2019): 7157. http://dx.doi.org/10.3390/su11247157.

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A rise in China’s economy and urbanization has brought about obvious growth in the carbon footprints of urban households over the past years. In this study, input–output analysis was adopted to calculate the carbon footprints of urban households in China. Furthermore, a detailed analysis of the impact factors on indirect carbon footprints was carried out by using the structural decomposition analysis at both holistic and sectoral levels. The results showed that the carbon footprints of urban households were 941.37 MtCO2 in 2002, 1498.11 MtCO2 in 2007, and 2139.50 MtCO2 in 2012. Electricity was the main contributor to the direct urban household carbon footprints, accounting for over 40%. The category of “household facilities” contributed the most to indirect carbon footprints (306.00 MtCO2) in 2012, and the “transportation” had the fastest growth rate (395%) during 2002–2012. The industrial sector of “wearing apparel” had the largest increments (139.92 MtCO2) in carbon footprints during the past decade. Generally, consumption level and population size presented positive effects on the increments in indirect carbon footprints, while emission intensity decreased indirect carbon footprints. However, the impact of consumption structure and intermediate demand on indirect carbon footprints varied at holistic and sectoral levels. The mitigation efforts should focus on reducing emission intensity, shifting consumption structure and changing intermediate demand.

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Luo, Haifeng. "Association between CNVs of BMI-related gene and survival status of LUAD and LUSC patients." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e20524-e20524. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20524.

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e20524 Background: In recent decades, many GWAS studies help to discover the gene related to BMI or obesity. FTO, BDNF, LEPR, MC4R, SH2B1, GNPDA2, INSIG2, KCTD15, LEP, MTCH2, NEGR1, NPC1, PCSK1, POMC, TMEM18 and UCP2 are 16 genes showing most significant association with BMI. Those genes impact BMI by either alternating sex hormone metabolism, influencing insulin and insulin-like growth factor, or mediating inflammatory and adipokines. Those pathways impact cancer cells also. Here we report the association between copy number variables (CNV) of those genes and outcome of lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). Methods: 522 individuals in LUAD dataset of TCGA and 504 individuals in LUSC dataset of TCGA are included in this study. CNVs of each gene are main predictors, the survival time is the main outcome in the study, and gender, tumor stage, smoking status are chosen to adjust model. Multivariable Cox models are generated for LUAD patients and LUSC patients respectively. To control false discovery rate (FDR), Benjamini-Hochberg procedure is employed. Results: For LUAD patients, tumor stages impact survival status significantly, but age, gender and smoking status don’t impact survival time significantly. At the same time, CNV of TMEM18 has hazard ratio of 0.0353 (95% CI: 0.0032, 0.3910), which means the gain of genetic materials on the position of TMEM18 gene will protect patients to die after diagnosis of LUAD, and the effect is extremely large. The p-value of 0.006 is less than 0.00625, which is derived with Benjamini-Hochberg procedure with false discovery rate of 0.1. For LUSC patients, only serious tumor stages, tumor stage III and tumor stage IV, impact survival status significantly, and old age will cause patients die earlier significantly. Neither gender nor smoking status don’t impact survival status significantly. When adjusting age, gender, smoking status, and tumor stage, gain of genetic materials on the position of NEGR1 gene does increase the risk of death significantly, and the hazard ratio of CNV of NEGR1 is 9.920 (95% CI: 1.237, 79.552). The p-value of 0.031 is large than 0.00625, which is derived with Benjamini-Hochberg procedure with fase discovery rate of 0.1. Conclusion: Copy number variable of TMEM18 gene impact outcome of LUAD patients significantly. The gain of TMEM18 genetic materials protects patients to die, meanwhile the loss of TMEM18 genetic materials cause patients to have shorter overall survival time. TMEM18 affect the central nervous system to imbalance energy metabolism in previous murine models, and here we found TMEM18 has significant impact on survival status of LUAD patients, so the transmembrane protein gene TMEM18 may be a key factor to outcome of LUAD.

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Vivid Amalia Khusna and Deni Kusumawardani. "Decomposition of Carbon Dioxide (CO2) Emissions in ASEAN Based on Kaya Identity." Indonesian Journal of Energy 4, no. 2 (August 31, 2021): 101–14. http://dx.doi.org/10.33116/ije.v4i2.122.

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ASEAN is a region with high carbon dioxide (CO2) emissions, accompanied by an increase in population, gross domestic product (GDP) and energy consumption. Population, GDP, and energy consumption can be linked to CO2 emissions through an identity equation called the Rich Identity. This research is based on Kaya identity to describe CO2 emissions to calculate the impact of population, economic activity, energy intensity and carbon intensity on CO2 emissions in ASEAN and 8 ASEAN countries (i.e., Indonesia, Malaysia, Singapore, Thailand, Philippines, Vietnam, Myanmar and Brunei Darussalam) from 1990 to 2017. The method used is the Logarithmic Mean Division Index (LMDI). The data used are from the International Energy Agency (IEA) and the World Bank. Four effects measured and main findings showed that population, economic activity and carbon intensity factor increased by 293.02 MtCO2, 790.0 MtCO2, and 195.51 MtCO2, respectively. Meanwhile, energy intensity effect made ASEAN's CO2 emissions decrease by 283.13 MtCO2. Regarding contributions to the increase in CO2 emissions in all ASEAN countries, the population effect increases CO2 emissions in all countries in ASEAN and the economic activity effect is also the same, except in Brunei Darussalam which makes CO2 emissions in this country decreased by 1.07 MtCO2. Meanwhile, the effects of energy and carbon intensity are different. The effect of energy intensity causes CO2 emissions in lower-middle income countries to decrease, while in upper-middle and high-income countries, it increases carbon emissions. In contrast to the effect of carbon intensity, that actually makes CO2 emissions increase in lower-middle income countries and reduces carbon emissions in upper-middle and high-income countries.

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Alatiq, Abdulrahman, Wail Aljedani, Abdullah Abussaud, Omar Algarni, Hélène Pilorgé, and Jennifer Wilcox. "Assessment of the carbon abatement and removal opportunities of the Arabian Gulf Countries." Clean Energy 5, no. 2 (June 1, 2021): 340–53. http://dx.doi.org/10.1093/ce/zkab015.

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Abstract The Arabian Gulf Countries (AGC) are strongly reliant on the economic export of fossil fuels, while being vulnerable to climate change that is resulting in temperature increase, air pollution and sea-level rise, and threatening the health of the population and ecosystem. In agreement with the Paris Accords, most of the AGC have published short-term goals to reduce their carbon emissions in the coming decades. In relation to these goals, this study explores the potential CO2 reduction, avoidance and removal in the region, by comparing a business-as-usual (BAU) scenario to three decarbonization scenarios for the power sector. In 2018, the total greenhouse gas (GHG) emissions in the AGC were ~1333 MtCO2/yr and are expected to rise to 1568 MtCO2/yr in 2030 following a BAU scenario, which is likely to be reduced to 1522 MtCO2/yr in 2030 by following the countries’ planning. Countries issued plans for the coming decades that focus on increasing the share of renewable energy in their grid mix. The three decarbonization scenarios presented in this study focus on supply-side technological solutions. The retirement of the oldest natural-gas and oil power plants could lead to a total emissions reduction of ~75 MtCO2/yr, without accounting for the embodied carbon emissions associated with renewable energy. In addition, the implementation of point-source capture at power plants expected to retire in >10 years’ time could avoid emissions of ~240 MtCO2/yr, provided the CO2 is permanently sequestered in appropriate geological formations. The region also shows high-quality solar resources and large CO2-storage potential that could couple to direct air-capture plants to offset difficult-to-avoid emissions. This last scenario has the potential to ultimately result in net negative emissions.

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Gultom, TH, D. Nugraha, Sugiyarno, and M. Iqbal. "Contribution of Obi Island Reducing the Carbon Footprint in the Transport Sector." IOP Conference Series: Earth and Environmental Science 1175, no. 1 (May 1, 2023): 012015. http://dx.doi.org/10.1088/1755-1315/1175/1/012015.

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Abstract Transportation is one of the main sectors contributing to greenhouse gas (GHG) emissions that cause global climate change. One of the decarbonization strategies from the transportation sector that can be implemented is by switching to a sustainable mode of transportation, especially battery electric vehicles (BEV). Since mid-2021, Obi Island has been producing Mixed Hydroxide Precipitate (MHP). It is an intermediate product of limonite nickel ore processed using hydrometallurgical processing techniques through the first refining plant in Indonesia using High Pressure Acid Leaching (HPAL) technology. The MHP will be processed into Nickel Sulfate (NiSO4.6H2O) and Cobalt Sulfate (CoSO4.7H2O), the primary precursor materials for electric vehicles. The potential GHG emissions reduction in the transportation sector from the processing of limonite nickel ore in Obi Island is 2.04 MtCO2 in 2022 to 21.02 MtCO2 in 2040 with a total accumulation until 2040 of 344.56 MtCO2.

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Ogasawara, Takashi, Masahiko Hatano, Hisae Satake, Jun Ikari, Toshibumi Taniguchi, Nobuhide Tsuruoka, Haruko Watanabe-Takano, et al. "Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells." Proceedings of the National Academy of Sciences 114, no. 5 (January 17, 2017): E741—E750. http://dx.doi.org/10.1073/pnas.1613528114.

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Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularlyInterleukin4(Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, includingIl4loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6’s association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.

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Lin, Yan-Ting, Wei Liu, Yun He, Yun-Li Wu, Wan-Nan Chen, Xin-Jian Lin, and Xu Lin. "Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes." Cellular Physiology and Biochemistry 51, no. 1 (2018): 80–96. http://dx.doi.org/10.1159/000495166.

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Background/Aims: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. Methods: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. Results: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. Conclusion: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.

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Journal articles on the topic 'MTCH2'

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