Review
Cell Biology
Edward V. Prochownik, Huabo Wang
Summary: Pyruvate plays a central role in metabolism, influenced by various cell-intrinsic and extrinsic factors. It is at the crossroads of glycolysis and the tricarboxylic acid cycle, with its production and fate being regulated by factors such as cell type, redox state, nutrient levels, and vascular supply. Six pathways impact pyruvate content and utilization, including lactate dehydrogenase pathway, alanine pathway, pyruvate dehydrogenase complex pathway, pyruvate carboxylase reaction, malic enzyme pathway, and acetate biosynthetic pathway. The review explores the mechanisms controlling these pathways and how they work together to achieve optimal growth and metabolic harmony.
Article
Biochemistry & Molecular Biology
Santiago Mansilla, Veronica Tortora, Florencia Pignataro, Santiago Sastre, Ignacio Castro, Ma. Laura Chiribao, Carlos Robello, Ari Zeida, Javier Santos, Laura Castro
Summary: Mitochondrial aconitase (ACO2) is a redox sensor in the tricarboxylic acid cycle, sensitive to reactive oxygen and nitrogen species due to its labile [4Fe-4S](2+) prosthetic group. It has been implicated in aging and pathologies related to mitochondrial dysfunction. Recombinant human ACO2 was expressed and characterized, showing high yield and determining kinetic parameters. ACO2 reacts with various reactive species with different rate constants, and its thermal stability is lower upon cluster oxidation. It was confirmed that frataxin (FXN) can reactivate [3Fe-4S](+)-ACO2 and directly interact with iron. Molecular dynamics simulations revealed differences in protein dynamics based on the Fe-S cluster redox state.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Review
Biology
Inseok Choi, Hyewon Son, Jea-Hyun Baek
Summary: The TCA cycle is a series of chemical reactions that occur in the mitochondria of aerobic organisms to generate energy from acetyl-CoA. The intermediates of the TCA cycle may leak from dysfunctional mitochondria and regulate immune responses under cell stress conditions. Increasing evidence suggests that the metabolites of the TCA cycle play important roles in the regulation of immune activation and suppression.
Article
Oncology
Yujiao Zhou, Haibo Yu, Shengtao Cheng, Yao Chen, Lin He, Jihua Ren, Xin He, Juan Chen, Lu Zheng, Fan Li
Summary: This study confirmed the glutamine addiction of HCC cells and found that the glutaminolysis pathway of HCC cells changed under different glucose conditions. When glucose was sufficient, the glutamate transaminases GOT1 pathway played a dominant role, while under glucose limitation, the deaminase GDH1 mediated metabolic pathway became dominant.
Review
Cell Biology
Peter S. Coleman, Risa A. Parlo
Summary: This passage discusses the interconnected networks of cell metabolism and the role of citrate within cells. It raises the question of the dilemma cells face in processing citrate metabolism and why cancer cells choose the glycolysis metabolic pathway.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Oncology
Qi Zhang, Longping Ma, Hongyuan Zhou, Yanzhao Zhou, Shuaijing Liu, Qiang Li
Summary: This study identified copper malnutrition-related genes affecting the TCA process and established a risk prognostic feature for predicting the prognosis of HCC patients. Patients in the high-risk group had significantly lower overall survival rates compared to those in the low-risk group.
FRONTIERS IN ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Agata Wawrzkiewicz-Jalowiecka, Anna Lalik, Agnieszka Lukasiak, Monika Richter-Laskowska, Paulina Trybek, Maciej Ejfler, Maciej Opalka, Sonia Wardejn, Domenico V. V. Delfino
Summary: Potassium channels are important proteins that shape the biology of cancer cells. Their relationship with K+ channel function, glucose metabolism, and cancer glycome is intriguing. This review outlines the interconnections between potassium channel expression and activity, carbohydrate metabolism, and altered glycosylation in cancer cells, and proposes potential mediators and novel directions for further research.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Guanqiao Chen, Xiaoshan Hong, Wanshan He, Lingling Ou, Bin Chen, Weitao Zhong, Yu Lin, Xiping Luo
Summary: This study aimed to identify genes related to the tricarboxylic acid (TCA) cycle as prognostic markers in cervical cancer (CC). Differential gene expression analysis was performed using data from The Cancer Genome Atlas (TCGA) database. A prognostic model consisting of seven TCA cycle associated genes (ACSL1, ALDOA, FOXK2, GPI, MDH1B, MDH2, and MTHFD1) was constructed. Patients with high risk scores had worse prognosis and lower sensitivity to conventional chemotherapy drugs. The expression of the prognostic gene signature was validated in clinical CC samples using quantitative polymerase chain reaction (qRT-PCR).
FRONTIERS IN GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Yuji Nagayama, Koichiro Hamada
Summary: This review provides an overview of essential metabolic mechanisms and summarizes recent findings on metabolic reprogramming and metabolism-targeted therapies for thyroid cancer.
Article
Multidisciplinary Sciences
Stefan Hintze, Lisa Baber, Fabian Hofmeister, Stefanie Jarmusch, Vanessa Todorow, Stefan Mehaffey, Fabiana Tanganelli, Uta Ferrari, Carl Neuerburg, Daniel Teupser, Martin Bidlingmaier, Jair Gonzalez Marques, Berthold Koletzko, Benedikt Schoser, Michael Drey, Peter Meinke
Summary: Severe cases of age-related loss of muscle function and mass are unique to sarcopenia. This study investigated the role of mitochondrial dysfunction in sarcopenia by analyzing muscle and serum samples from hip fracture patients. The results showed a correlation between high sarcopenia Z-scores and reduced mitochondrial complex I activity, increased tricarboxylic acid cycle metabolites, reduced vitamin D3 levels, and signs of altered iron metabolism. The study suggests that a combination of factors, including vitamin D3 deficiency and disturbances in iron metabolism, contribute to complex I deficiency and muscle weakness in sarcopenia.
Article
Cell Biology
Feng Cai, Divya Bezwada, Ling Cai, Rohit Mahar, Zheng Wu, Mario C. Chang, Panayotis Pachnis, Chendong Yang, Sherwin Kelekar, Wen Gu, Bailey Brooks, Bookyung Ko, Hieu S. Vu, Thomas P. Mathews, Lauren G. Zacharias, Misty Martin-Sandoval, Duyen Do, K. Celeste Oaxaca, Eunsook S. Jin, Vitaly Margulis, Craig R. Malloy, Matthew E. Merritt, Ralph J. Deberardinis
Summary: Stable isotopes are important tools for evaluating metabolism and can be detected using both mass spectrometry and nuclear magnetic resonance in vivo. We have developed a mass spectrometry method that can report all 16 aspartate and 32 glutamate isotopomers, offering higher sensitivity than nuclear magnetic resonance. This method allows for discrimination between pathways that result in the same number of 13C labels in aspartate and glutamate. Through experiments, we have demonstrated metabolic heterogeneity within human tumors, examined the impact of fumarate hydratase deficiency in renal cancer, and investigated the contributions of tricarboxylic acid cycle turnover and CO2 recycling to in vivo isotope labeling.
Article
Neurosciences
Dongdong Jia, Fangzhou Wang, Haitao Yu
Summary: Mitochondrial dysfunction, particularly TCA cycle arrest, is closely related to Alzheimer's disease (AD). This study analyzed the transcriptomics of AD brain and peripheral blood cells to identify the expression levels of TCA cycle enzymes. The results showed consistent down-regulation of TCA cycle genes in the AD brain, while there were alterations in 11 genes in the peripheral system. Pearson analysis revealed significant correlations between TCA cycle genes and AD-related markers. Several genes, including PDHB, SUCLA2, and MDH1, were uniformly down-regulated in peripheral blood cells, suggesting their potential as diagnostic markers for AD.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Plant Sciences
Younes Dellero, Solenne Berardocco, Cecilia Berges, Olivier Filangi, Alain Bouchereau
Summary: The estimation of metabolic fluxes in photosynthetic organisms is a significant challenge, especially with the development of C-13-Metabolic Flux Analysis. To accurately measure Carbon Isotopologue Distribution and minimize uncertainties for the calculated fluxes, the accuracy of GC-MS at the isotopologue level needs to be evaluated. This study developed a workflow to validate GC-MS measurements of Carbon Isotopologue Distributions in plant metabolites by using standardized extracts and investigated the light/dark regulation of the TCA cycle in Brassica napus leaf discs. The findings showed the cyclic operation of the TCA cycle under both light and dark conditions, with interesting contributions of different pathways and reassimilation of carbon derived from mitochondrial enzymes.
FRONTIERS IN PLANT SCIENCE
(2023)
Article
Endocrinology & Metabolism
Xin You, Jingyu Tian, Hui Zhang, Yunhua Guo, Jing Yang, Chaofeng Zhu, Ming Song, Peng Wang, Zexian Liu, John Cancilla, Wenhua Lu, Christophe Glorieux, Shijun Wen, Hongli Du, Peng Huang, Yumin Hu
Summary: The study revealed an association between reduced mitochondrial aconitase (ACO2) levels in colorectal cancer (CRC) with advanced disease stage and shorter patient survival. Knockdown of ACO2 promoted cell proliferation and tumor formation, while overexpression of ACO2 restrained tumor growth. Loss of ACO2 led to decreased TCA cycle intermediates, increased glycolysis, and elevated citrate flux for fatty acid synthesis.
MOLECULAR METABOLISM
(2021)
Article
Pharmacology & Pharmacy
Chujiao Hu, Zhirui Zeng, Dan Ma, Zhixin Yin, Shanshan Zhao, Tengxiang Chen, Lei Tang, Shi Zuo
Summary: In this study, novel inhibitors of IDH1-R132C were identified using virtual screening and cellular assays. Compound T001-0657 showed the most potent inhibitory effect against cancer cells harboring the IDH1-R132C mutation, while also exhibiting cytotoxicity against wild-type IDH1 cancer cells and normal cells.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Huabo Wang, Jie Lu, James Dolezal, Sucheta Kulkarni, Weiqi Zhang, Angel Chen, Joanna Gorka, Jordan A. Mandel, Edward V. Prochownik
Article
Biochemistry & Molecular Biology
Huabo Wang, Jie Lu, Xiaoguang Chen, Marie Schwalbe, Joanna E. Gorka, Jordan A. Mandel, Jinglin Wang, Eric S. Goetzman, Sarangarajan Ranganathan, Steven F. Dobrowolski, Edward Prochownik
Summary: Metabolic reprogramming in transformed cells provides them with proliferative and survival advantages, but therapeutic applications have been limited by small differences in metabolic pathways and cancer adaptation. However, experiments have shown that downregulation of Ehhadh in hepatoblastoma makes them more susceptible to dietary intervention with C12, leading to longer survival and potential resistance development. This research suggests the feasibility of non-toxic dietary supplementation with C12 or DDDA, which may be compatible with standard chemotherapies.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Gastroenterology & Hepatology
Huabo Wang, Jie Lu, Jordan A. Mandel, Weiqi Zhang, Marie Schwalbe, Joanna Gorka, Ying Liu, Brady Marburger, Jinglin Wang, Sarangarajan Ranganathan, Edward Prochownik
Summary: The study found that the mutations of NFE2L2 and key transcripts, including Serpin E1, directly contribute to the specific features of hepatoblastoma.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2021)