bims-meprid 2023-07-30 papers

Issue of 2023‒07‒30
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Cell Discov. 2023 Jul 25. 9(1): 76

The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth.

Xiaojun Ren, Jimei Yan, Qiongya Zhao, Xinzhu Bao, Xinyu Han, Chen Zheng, Yan Zhou, Lifang Chen, Bo Wang, Lina Yang, Xi Lin, Dandan Liu, Yuyan Lin, Min Li, Hezhi Fang, Zhimin Lu, Jianxin Lyu.

IscU2 is a scaffold protein that is critical for the assembly of iron-sulfur (Fe-S) clusters and the functions of Fe-S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe-S cluster and regulates the activity of tricarboxylic acid (TCA) cycle enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

DOI: https://doi.org/10.1038/s41421-023-00558-8

J Heart Lung Transplant. 2023 Jul 24. pii: S1053-2498(23)01940-X. [Epub ahead of print]

MTHFD2 Ablation in T Cells Protects against Heart Transplant Rejection by Perturbing IRF4/PD-1 Pathway through the Metabolic-epigenetic Nexus.

Yuan Li, Zhang Chen, Jikai Cui, Jizhang Yu, Yuqing Niu, Shuan Ran, Song Wang, Weicong Ye, Heng Xu, Xi Zhang, Jie Wu, Jiahong Xia.

BACKGROUND: One-carbon metabolism supports the activation, proliferation, and function of multiple immune cells. However, researchers have not clearly determined whether and how one-carbon metabolic enzymes contribute to heart transplant rejection.METHODS: We investigated the dynamic metabolic adaptation in grafts during heart transplant rejection by conducting transcriptomics, metabolomics and single-cell RNA sequencing studies of cardiac tissue from human and mouse heart transplant recipients. We also assessed the expression of the one-carbon metabolic enzyme MTHFD2 in cardiac grafts by immunofluorescence and flow cytometry assays. Then we constructed a murine heart transplant model with T cell-specific Mthfd2 knockout mice, analyzed T cells function by flow cytometry assays and enzyme-linked immunospot assays, and studied the mechanism by Cleavage Under Targets and Tagmentation assays. Finally, we studied the effect of a pharmacological inhibitor of MTHFD2 in humanized skin transplant model.
RESULTS: We revealed that the one-carbon metabolism enzyme MTHFD2 was a hallmark of alloreactive T cells and was linked to T cell proliferation and function after exposure to alloantigen. And, Mthfd2 ablation prevented murine heart transplant rejection. Mechanistically, we found Mthfd2 ablation affected the IRF4/PD-1 pathway through a metabolic-epigenetic mechanism involving H3K4me3. Furthermore, we found that inhibiting MTHFD2 attenuated human allograft rejection in a humanized skin transplant model.
CONCLUSIONS: These data show that the one-carbon metabolic enzyme MTHFD2 serves as a metabolic checkpoint of alloreactive T cells and suggest that it may be a potential therapeutic target for heart transplant rejection.

Keywords: Heart transplant rejection; IRF4; MTHFD2; One-carbon metabolism; T cells

DOI: https://doi.org/10.1016/j.healun.2023.07.009

Res Sq. 2023 Jul 10. pii: rs.3.rs-3029860. [Epub ahead of print]

Repression of ferroptotic cell death by mitochondrial calcium signaling.

Haitao Wen, Jianwen Chen, Bao Zhao, Shen Wang, Anjun Ma, Hong Dong, Xiang Cheng, Shengyin Lin, Xinghui Li, Laura Herring, Gang Xin, Qin Ma, Kai He, Ruili Xie, Yu Lei, Irina Ingold, Xiaolin Cheng, Zihai Li.

The uptake of Ca 2+ into and extrusion of calcium from the mitochondrial matrix, regulated by the mitochondrial Ca 2+ uniporter (MCU), is a fundamental biological process that has crucial impacts on cellular metabolism, signaling, growth and survival. Herein, we report that the embryonic lethality of Mcu -deficient mice is fully rescued by orally supplementing ferroptosis inhibitor lipophilic antioxidant vitamin E and ubiquinol. Mechanistically, we found MCU promotes acetyl-CoA-mediated GPX4 acetylation at K90 residue, and K90R mutation impaired the GPX4 enzymatic activity, a step that is crucial for ferroptosis. Structural analysis supports the possibility that GPX4 K90R mutation alters the conformational state of the molecule, resulting in disruption of a salt bridge formation with D23, which was confirmed by mutagenesis studies. Finally, we report that deletion of MCU in cancer cells caused a marked reduction in tumor growth in multiple cancer models. In summary, our study provides a first direct link between mitochondrial calcium level and sustained GPX4 enzymatic activity to regulate ferroptosis, which consequently protects cancer cells from ferroptosis.

DOI: https://doi.org/10.21203/rs.3.rs-3029860/v1

bioRxiv. 2023 Jul 23. pii: 2023.07.18.549409. [Epub ahead of print]

Loss of the mitochondrial citrate carrier, Slc25a1/CIC disrupts embryogenesis via 2-Hydroxyglutarate.

Anna Kasprzyk-Pawelec, Mingjun Tan, Yu Leng Phua, Raneen Rahhal, Alec McIntosh, Harvey Fernandez, Rami Mosaoa, Michael Girgis, Amrita Cheema, Lei Jiang, Lawrence F Kroemer, Anastas Popratiloff, Cheryl Clarkson, Brian M Kirmsa, Gray W Pearson, Eric Glasgow, Christopher Albanese, Jerry Vockley, Maria Laura Avantaggiati.

Biallelic germline mutations in the SLC25A1 gene lead to combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a fatal systemic disease uniquely characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). How SLC25A1 deficiency contributes to D/L-2HGA and the role played by 2HG is unclear and no therapy exists. Both enantiomers act as oncometabolites, but their activities in normal tissues remain understudied. Here we show that mice lacking both SLC25A1 alleles exhibit developmental abnormalities that mirror human D/L-2HGA. SLC25A1 deficient cells undergo premature mitochondrial dysfunction associated senescence, suggesting that loss of proliferative capacity underlies the pathogenesis of D/L-2HGA. Remarkably, D- and L-2HG directly induce mitochondrial respiratory deficit and treatment of zebrafish embryos with the combination of D- and L-2HG phenocopies SLC25A1 loss, leading to developmental abnormalities in an additive fashion relative to either enantiomer alone. Metabolic analyses demonstrated that loss of SLC25A1 leads to global remodeling towards glutamine metabolism, with glutamine serving as a source for 2HG synthesis. Therefore, we explored the pre-clinical relevance of phenylbutyrate, an FDA-approved drug that reduces the blood glutamine levels, and found that it reduces 2HG accumulation reversing metabolic abnormalities in patients affected by D/L-2HGA. These results reveal pathogenic and growth suppressive activities of 2HG in the context of SLC25A1 deficiency and expose metabolic vulnerabilities for the clinical management of this disease.

DOI: https://doi.org/10.1101/2023.07.18.549409

Genes Dis. 2023 Sep;10(5): 2029-2037

The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Yan Zhang, Qiu Peng, Jinhua Zheng, Yuzhong Yang, Xuemei Zhang, Aiyu Ma, Yuxia Qin, Zailong Qin, Xiang Zheng.

Lactate is an end product of glycolysis. Owing to the lactate shuttle concept introduced in the early 1980s, increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells, resulting in diverse biological consequences including decreased lipolysis, immune regulation, and anti-inflammation wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, which accounts for its key role in immune modulation and maintenance of homeostasis. Here, we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Keywords: Epigenetic regulation; Lactate; Lactylation; Microenvironment; Tumorigenesis

DOI: https://doi.org/10.1016/j.gendis.2022.10.006