Ferrous Fumarate

引言 三羧酸循环（TCA cycle）是糖类、脂类、氨基酸三大营养物质氧化分解的共同途径，也是糖、脂肪、 氨基酸代谢联系的枢纽，为机体提供能量和生物合成的前体分子。苹果酸酶（哺乳动物细胞内存在ME1，ME2 和ME3三种异构体，其中ME1和ME2是主要形式）将TCA循环的中间产物苹果酸转化为丙酮酸并伴随NAD(P)H产生，是三羧酸循环的重要补充反应，使细胞在能量、还原当量和生物合成前体需求之间保持一定的平衡，因此，苹果酸酶代谢是细胞内代谢途径的重要交汇途径。 为了系统揭示苹果酸酶代谢的生理病理功能，中国医学科学院基础医学研究所杜文静教授课题组近年来一直聚焦于不同环境和条件下苹果酸代谢的功能和调控机制研究。该组研究人员在2021年发表于Nature Metabolism的研究发现苹果酸酶代谢产生的NADPH直接结合并抑制HDAC3的活性，从而调控了细胞的表观遗传状态，该研究揭示了NADPH代谢非依赖的新功能【1】。在2022年发表于Nature Metabolism的研究工作发现苹果酸酶ME2通过调控细胞内2-羟基戊二酸（2-HG）的生成，维持突变体p53的蛋白稳定性，从而促进肿瘤细胞生长，该研究发现了ME2在细胞内的一种新的催化活性【2】。在2023年发表于PNAS的研究工作发现ME2作为MYC转录上调的靶基因，通过介导谷氨酰胺代谢维持细胞内的氧化还原平衡，在T细胞淋巴瘤的发生发展中具有重要作用。同年，发表在Cell Reports的研究工作发现ME2通过αKG介导的cyclin D1的转录来促进细胞周期的进展，该研究揭示了αKG在调节细胞周期基因转录中的新功能【4】。此外，该课题组于2024年1月发表在Nature Communications的研究工作发现ME2 的一个新形式——细胞质形式 ME2fl， AKT1 的激活通过细胞质ME2（ME2fl）的磷酸化诱导代谢从线粒体代谢转向糖酵解，从而有利于增强细胞的糖酵解表型，该研究揭示了AKT1 介导的 ME2 亚细胞转位转换在肿瘤细胞适应生长刺激的代谢过程中发挥了意想不到的作用【5】。 2024年8月15日，杜文静教授课题组在Molecular cell杂志发表了题为Malic Enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells（苹果酸酶2维持CD8+ T细胞的代谢稳态和抗肿瘤免疫能力）的研究论文。 在该研究工作中，研究人员首先构建了苹果酸酶2（ME2） T细胞条件性基因敲除小鼠（CD4-Cre;ME2fl/fl mice），发现与野生型小鼠 （ME2 WT）相比，T细胞中缺失ME2表达的小鼠（ME2 KO）具有较弱的肿瘤抑制能力。通过CD4+ / CD8+ T细胞清除实验和细胞过继实验发现，ME2主要调控CD8+ T细胞（而非CD4+ T细胞）的效应性功能和抗肿瘤免疫能力。代谢组学和代谢流分析发现，ME2缺失阻断了CD8+ T细胞的三羧酸（TCA）循环，导致了TCA中间代谢产物fumarate在细胞内的堆积。详细的分子机制研究发现，fumarate能够直接结合DAPK1，并通过与ATP竞争结合来抑制DAPK1的激酶活性，从而抑制了其下游的TSC2-mTORC1信号通路，导致CD8+ T 细胞的活化、效应功能和抗肿瘤作用也相应降低。当DAPK1或mTORC1被抑制时，ME2失去了对CD8+ T细胞抗肿瘤功能的影响。相反，过表达持续活化的DAPK1几乎完全恢复了ME2缺失的CD8+ T细胞的抗肿瘤能力。这些结果表明，DAPK1是ME2赋予CD8+ T细胞效应功能和抗肿瘤作用的关键下游靶点，ME2 通过fumarate调控的 DAPK1-TSC2-mTORC1 信号轴调节 CD8+ T 细胞功能。 此外，与之前的研究一致，本研究也发现了fumarate抑制 CD8+ T 细胞的活化和抗肿瘤能力。然而，之前研究发现，fumarate对 T 细胞的抑制作用是通过可逆地抑制参与表观遗传信号转导的二氧酶【6】或通过蛋白质的琥珀酸化修饰实现的【7】。本研究发现fumarate是一种调节 CD8+ T 细胞中 DAPK1 活性的信号分子。fumarate直接与 DAPK1 的 ATP 口袋结合，并通过与 ATP 竞争来抑制 DAPK1 的活性。fumarate对 DAPK1 活性的抑制作用取决于fumarate/ATP 的比例，这表明fumarate可能作为 ATP 拮抗剂来调节 DAPK1 的活性。值得注意的是，先前的一项研究表明，DMF 通过琥珀酸化糖酵解代谢酶GAPDH抑制髓系和淋巴细胞的有氧糖酵解【8】。然而 ME2 的缺失对 CD8+ T 细胞的糖酵解通并没有影响，这表明 ME2缺失导致的fumarate积累不会影响糖酵解。因此，虽然fumarate对 T 细胞活化有类似的抑制作用，但其通过不同的机制发挥其功能，这很可能是条件依赖性的。例如，ME2 缺乏导致的fumarate积累水平可能不足以琥珀酸化 GAPDH 来抑制糖酵解，但它可以抑制 DAPK1 的活性，进而抑制 CD8+ T 细胞的活化。因此，该研究表明，DAPK1可能是fumarate的感受器，对细胞fumarate水平的变化更为敏感，从而控制CD8+ T细胞的命运。 模式图（Credit: Molecular cell） 综上所述，本研究发现了ME2 在 T 细胞中的作用，ME2 缺乏会导致fumarate在 CD8+ T 细胞中积累，进而通过抑制 DAPK1 来阻碍 mTORC1 信号传导，导致 CD8+ T 细胞的效应功能和抗肿瘤效果受损。值得注意的是，该课题组之前的研究表明，ME2的表达水平和酶活性在T细胞淋巴瘤中上调，对T细胞淋巴瘤的发生至关重要【3】，而本研究表明，ME2的生理功能是维持CD8+ T细胞新陈代谢所必需的。这些发现共同凸显了 ME2 在 T 细胞生理和病理过程中的重要性。 参考文献 1. Li, W., Kou, J., Qin, J., Li, L., Zhang, Z., Pan, Y., Xue, Y., and Du, W. (2021). NADPH levels affect cellular epigenetic state by inhibiting HDAC3-Ncor complex. Nat Metab 3, 75-89. 2. Zhao, M., Yao, P., Mao, Y., Wu, J., Wang, W., Geng, C., Cheng, J., Du, W., and Jiang, P. (2022). Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate. Nat Metab 4, 225-238. 3. Li, W., Kou, J., Zhang, Z., Li, H., Li, L., and Du, W. (2023). Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis. Proc Natl Acad Sci U S A 120, e2217869120. 4. Yang, Y., Zhang, Z., Li, W., Si, Y., Li, L., and Du, W. (2023). alphaKG-driven RNA polymerase II transcription of cyclin D1 licenses malic enzyme 2 to promote cell-cycle progression. Cell Rep 42, 112770. 5. Chen, T., Xie, S., Cheng, J., Zhao, Q., Wu, H., Jiang, P., and Du, W. (2024). AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis. Nat Commun 15, 686. 6. Zhai, X., Liu, K., Fang, H., Zhang, Q., Gao, X., Liu, F., Zhou, S., Wang, X., Niu, Y., Hong, Y., et al. (2021). Mitochondrial C1qbp promotes differentiation of effector CD8(+) T cells via metabolic-epigenetic reprogramming. Sci Adv 7, eabk0490. 7. Cheng, J., Yan, J., Liu, Y., Shi, J., Wang, H., Zhou, H., Zhou, Y., Zhang, T., Zhao, L., Meng, X., et al. (2023). Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8(+) T cells in the tumor microenvironment. Cell Metab 35, 961-978 e910. 8. Kornberg, M.D., Bhargava, P., Kim, P.M., Putluri, V., Snowman, A.M., Putluri, N., Calabresi, P.A., and Snyder, S.H. (2018). Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449-453. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.molcel.2024.07.021 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

Researchers share new findings on caring for preterm babies, children with cancer, and young people with sickle cell disease NEW ORLEANS, Dec. 12, 2022 /PRNewswire/ -- New research being presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition draws attention to previously overlooked issues in caring for babies and young people and sheds light on opportunities to improve the outlook for children with health challenges. "These studies can inform ways to help children live long and healthy lives," said press briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children's National in Washington, DC. "They will certainly be of interest to clinicians, and also to the families of children dealing with blood disorders or requiring special care." The first study expands the body of knowledge on long-term health outcomes of childhood cancer treatment, pointing to new opportunities for screening and early detection while underscoring the importance of finding gentler therapies that could help more children avoid these long-term health problems in the first place. In the second study, researchers report that preterm babies who are fed only formula show a higher risk of iron deficiency, suggesting that new guidance on feeding practices may be warranted to ensure all preterm babies maintain sufficient iron levels necessary for growth and development. The third study highlights how a data-sharing system could help people with sickle cell disease avoid dangerous blood transfusion complications and allow more young people to benefit from future curative therapies for this disease later in life. Together, the studies highlight the challenges in and opportunities for improving care for babies and young people. The press briefing will take place on Monday, December 12, at 12:00 noon Central time in press briefing room 346. Study links accelerated aging in survivors of childhood Hodgkin lymphoma with neurocognitive impairment in middle age 902: Epigenetic Age Acceleration and Neurocognitive Function Among Long-Term Survivors of Pediatric Hodgkin Lymphoma: A Report from the St. Jude Lifetime Cohort In a new study, people treated for Hodgkin lymphoma in childhood showed accelerated aging and had higher rates of neurocognitive impairment by their late 30s compared to their peers. The study analyzed "biologic age," a marker of changes to gene expression that accrue over a person's lifetime, based on the level of DNA methylation measured in blood samples. The findings suggest childhood cancer survivors may benefit from additional screening or interventions to mitigate aging-related cognitive declines starting in early adulthood. "We found that biologic aging is associated with long term neurocognitive impairment in Hodgkin lymphoma survivors," said AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester School of Medicine and Dentistry in New York. "Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging." The study involved nearly 500 participants in their late 30s; 215 were survivors of childhood Hodgkin lymphoma and 282 did not have cancer in childhood. Participants submitted blood samples and underwent a series of validated neurocognitive tests to assess attention, processing speed, memory, and executive function. Researchers found that the difference between biologic age and chronologic age was on average 7.7 years greater among Hodgkin lymphoma survivors compared with the control group, suggesting that their cancer or cancer treatment prematurely accelerated their aging. Overall, more than 80% of Hodgkin lymphoma survivors showed evidence of accelerated epigenetic aging compared with just 23% in the control group. Among survivors of childhood Hodgkin lymphoma, those with more accelerated epigenetic aging performed significantly worse in terms of memory, learning, attention, and executive function compared with those who had less evidence of premature aging. Although the observed degree of impairment may not be readily apparent to friends or family members, researchers said it was clinically significant and could likely be noticed by the survivors themselves, in instances such as small lapses in memory. "These types of memory issues are something people tend to notice first with aging-related disorders like Alzheimer's and dementia," said Dr. Williams. "I hope our study brings awareness to the fact that these underlying biologic changes are not only associated with heart disease and other chronic conditions that we have been aware of in survivors, but also with poor neurocognitive function." The association likely reflects the long-term effects of cancer treatments rather than the cancer itself, researchers said. They noted that treatment regimens used today are somewhat different from those several decades ago, so children currently being treated for cancer now may not necessarily develop the same degree of accelerated aging. The researchers are continuing the study to examine changes over time. Other related studies are examining rates of early-onset dementia and Alzheimer's disease in survivors of childhood cancer. AnnaLynn M. Williams, University of Rochester School of Medicine and Dentistry, will present this study during an oral presentation on Monday, December 12, 2022, at 3:00 p.m. Central time in 291-292. Formula-fed preterm babies are at a higher risk of iron deficiency than breastfed babies 3638: Formula Feeding Significantly Increases Risk of Iron Deficiency in Very Preterm Infants during the First 4-6 Months of Life Among babies born before 31 weeks gestation (considered "very preterm"), those fed only with formula were more likely to have iron deficiency even though they had higher iron intake than babies who were breastfed, according to a study conducted in Canada. Iron deficiency in infancy is associated with cognitive, social, and emotional problems later in life. "Just because a baby is on iron-rich formula, we should not assume all of their iron needs are being met, since iron from the formula may not have the same absorption as iron from breast milk," said Grace Power, a third-year medical student at Dalhousie University in Nova Scotia, Canada. "These findings suggest we might need to rethink some of the guidelines for iron supplementation." Since formula contains more iron than breast milk, the Canadian Pediatric Society has issued guidance recommending iron supplementation for breastfed but not formula-fed preterm babies; however, to date there has been little research into how feeding type influences the iron stores in these babies. The American Academy of Pediatrics doesn't offer guidance on iron supplementation in preterm babies with respect to the type of feeding. For the study, researchers analyzed health records from 392 very preterm infants born in Nova Scotia from 2005-2018. Since all preterm babies born in the province are followed through a single medical center, the data set is considered to be representative of the general Canadian population in terms of patient demographics and health care protocols. About three-quarters were exclusively fed iron-rich formula and one-quarter were partially or exclusively breastfed. Researchers extracted data on feeding practices, iron intake from formula and iron supplements, and iron levels in the blood taken at four and six months of age (with ages corrected for prematurity by subtracting the number of weeks early each baby was born from its actual age). The study revealed that babies who were exclusively formula-fed had a significantly higher daily iron intake than babies who were breastfed. Nonetheless, more than 36% of formula-fed babies and just over 20% of breastfed babies were iron deficient, suggesting that higher iron intake in formula does not always translate into higher iron stores in the blood. Researchers said one likely explanation is that components of breast milk that are not found in formula, such as hormones, help to increase the absorption of iron into the baby's bloodstream. Even consuming a mix of breast milk and formula was found to be protective, indicating that exclusive breastfeeding is not required for babies to derive this benefit. Formula-fed babies who were born earlier, those who were born smaller, and those who had received blood transfusions, were found to be at greater risk for iron deficiency than other formula-fed infants. "We should not assume a one-size-fits-all approach to iron supplementation," said Ms. Power. While more research is needed to inform future guidelines, in the meantime, Ms. Power suggested that preterm babies could benefit from closer monitoring, especially those who are exclusively fed formula. "If iron stores are checked in time and babies are regularly supplemented with iron as needed, we can still prevent iron deficiency." Too much iron can also be harmful, so researchers cautioned that careful monitoring is important to ensure the right balance. Future studies on the topic could help confirm the findings and inform future guidelines, researchers noted. Grace Power, Dalhousie University, will present this study during a poster presentation on Monday, December 12, 2022, at 6:00 p.m. Central time in Hall D. National system for sharing data from blood transfusions would save lives and money, according to projections 885: A US-Wide Red Blood Cell Alloantibody Exchange Can Decrease Mortality and Produce Cost Savings in the Care of Alloimmunized Patients with Sickle Cell Disease Getting a blood transfusion can be life-saving, but it also carries the risk of a dangerous immune reaction, especially for people who have received a previous blood transfusion or have been pregnant. According to projections from a new study, establishing a central repository to share data on patients' blood antibodies would not only significantly reduce the risks patients face but also cut health care costs by helping patients avoid prolonged hospitalization for serious transfusion complications. "The findings from our model are pretty definitive," said George Goshua, MD, MSc, Yale University School of Medicine in Connecticut. "Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction, or DHTR." A DHTR occurs when transfused blood triggers an immune response in the days or weeks following a blood transfusion. It results from the presence of proteins called alloantibodies, which can circulate in the blood after a pregnancy or previous blood transfusion. Although rare, DHTRs can be fatal and often require prolonged hospitalization, making them burdensome for patients, families, and health systems. To confirm that the blood selected for transfusion is likely to be safe for a patient and prevent DHTRs, doctors can check donated blood against the patient's alloantibody profile. While the information needed to do this often exists, it is typically not shared between different health systems in the United States, leaving doctors to select blood without access to this critical information. For the study, researchers used a computer simulation to estimate the costs and benefits of establishing a U.S. alloantibody exchange – a central repository for alloantibody data that doctors could access from any U.S. health care system. They estimated how such a repository would affect DHTR mortality and associated health care costs among people with sickle cell disease (SCD), who face a particularly high rate of DHTRs due to their relatively frequent need for blood transfusions. The results project that an alloantibody exchange would significantly reduce the cumulative lifetime risk of dying from a DHTR from 5.7% to 2.4% for people with SCD who have alloantibodies and bring a cumulative net savings of up to $1.5 billion over the lifetime of the population of such individuals in the U.S. today. The study provides a conservative estimate of benefits since it did not account for benefits in people who require blood transfusions for conditions other than SCD. Researchers noted that an alloantibody exchange would also help to reduce health risks and care costs among other patient populations not included in the model, such as people who require blood transfusions during cancer treatment. "It's saying that we can do two things at the same time – we can save lives and save costs," said Dr. Goshua, whose lab is the first in the U.S. focused on quantitative decision analytic modeling in classical (non-malignant) hematology. "It should be a no-brainer." The researchers also found their model's calculations were comparable to the demonstrated benefits of a real-world alloantibody exchange in the Netherlands, offering further validation of the study findings. George Goshua, MD, MSc Yale University School of Medicine, will present this study during an oral presentation on Monday, December 12, 2022, at 3:15 p.m. Central time in New Orleans Theater C. Additional press briefings will take place throughout the meeting on health equity, advances in blood cancer research and care, novel drug development, and selected late-breaking abstracts. For the complete annual meeting program and abstracts visit . Follow ASH and #ASH22 on Twitter, Instagram, LinkedIn, and Facebook for the most up-to-date information about the 2022 ASH Annual Meeting. The American Society of Hematology (ASH) () is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH's flagship journal, Blood (), is the most cited peer-reviewed publication in the field, and Blood Advances (), is the Society's online, peer-reviewed open-access journal. SOURCE American Society of Hematology